Substituted 1,2,3-triazoles as SMYD inhibitors for treating cancer

ABSTRACT

The present disclosure provides carboxamides and sulfonamides having Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, Y, B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure provides carboxamides and sulfonamides as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit.

Background

Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., SMYD proteins such as SMYD3 and SMYD2), many of which are associated with genetic alterations that can cause human disease, such as proliferative disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of SMYD proteins such as SMYD3 and SMYD2.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides carboxamido and sulfonamide compounds represented by Formulae I-XVIII below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as “Compounds of the Disclosure.”

In another aspect, the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.

In another aspect, the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.

In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.

In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.

In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD proteins.

In another aspect, the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.

In another aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.

In another aspect, the present disclosure provides kit comprising a Compound of the Disclosure.

Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD proteins. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD proteins.

One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD3.

One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.

In one embodiment, Compounds of the Disclosure are compounds having Formula I:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:

A is selected from the group consisting of 1,2,3-triazolyl, 1,2,4-triazolyl, 1-imidazolyl, 1-isoquinolinyl, 1-pyrazolyl, 2-(1,2,3,4-tetrahydroquinolinyl), 2-benzo[d]imidazolyl, 2-benzo[d]thiazolyl, 2-chromenyl-4-one, 2-furanyl, 2-imidazo[1,2-b]pyridazinyl, 2-imidazolyl, 2-indolyl, 2-naphthalenyl, 2-pyrazinyl, 2-pyridyl, 2-pyrimidinyl, 2-pyrrolidinyl, 2-pyrrolyl, 2-quinolinyl, 2-quinoxalinyl, 2-thiazolo[5,4-c]pyridinyl, 2-thiazolyl, 2-thiophenyl, 3-(1,2,3,4-tetrahydroisoquinoline), 3-(1,2,4-oxadiazolyl), 3-imidazo[1,2-a]pyrimidinyl, 3-indazolyl, 3-indolyl, 3-isothiazolyl, 3-pyrazolyl, 3-pyridazinyl, 3-pyridinyl-2-one, 3-pyridyl, 3-pyrrolo[3,2-b]pyridinyl, 3-quinolinyl, 4-(2,2-difluorobenzo[d][1,3]dioxolyl), 4-cyclohexanyl-1-amine, 4-imidazolyl, 4-indolinyl-2-one, 4-indolyl, 4-isothiazolyl, 4-oxazolyl, 4-piperidinyl, 4-pyrazolyl, 4-pyridyl, 4-quinolinyl, 5-(1,3-dihydro-2H-benzo[d]imidazolyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-b]pyridinyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-c]pyridinyl-2-one), 5-(2,2-difluorobenzo[d][1,3]dioxolyl), 5-(2,4-dihydro-3H-1,2,4-triazolyl-3-one), 5-4H-furo[3,2-b]pyrrolyl, 5-benzo[c][1,2,5]oxadiazolyl, 5-benzo[d][1,3]dioxolyl, 5-benzo[d]oxazolyl-2(3H)-one, 5-bicyclo[2.2.1]heptyl-2-ene, 5-indolinyl-2,3-dione, 5-indolinyl-2-one, 5-indolyl, 5-isoindolinyl-1-one, 5-isoxazolyl, 5-pyrazolo[3,4-c]pyridinyl, 5-pyrazolyl, 5-pyrimidinyl, 5-thiazolyl, 6-(1,2,3,4-tetrahydronaphthalenyl), 6-(3,4-dihydroquinolinyl-2(1H)-one), 6-(3,4-dihydroquinoxalinyl-2(1H)-one), 6-(4,5-dihydropyridazinyl-3 (2H)-one), 6-benzo[b][1,4]oxazinyl-3-one, 6-benzo[d]imidazolyl, 6-benzo[d]oxazolyl-2(3H)-one, 6-benzo[d]thiazolyl, 6-chromenyl-2-one, 6-imidazo[2,1-b]thiazole, 6-indazolyl, 6-indolinyl-2-one, 6-indolyl, 6-isoquinolinyl, 6-quinolinyl, 6-quinoxalinyl, 6-quinoxalinyl-2(1H)-one, 7-(3,4-dihydroquinolinyl-2(1H)-one), 7-(3,4-dihydroquinoxalin-2(1H)-one), 7-benzo[b][1,4]oxazinyl-3-one, 7-indolinyl-2-one, 7-quinolinyl, 8-benzo[b][1,4]oxazinyl-3-one, cyclopropanyl, phenyl, 4-(prop-1-en-1-yl)-imidazole, 1-butanyl-imidazole, sec-butylcyclopropane, 2-(ethylsulfonyl)propanyl, 1-isobutylpyrrolidine, 4-pyridyl 1-oxide, and 5-benzo[c][1,2,5]oxadiazolyl 1-oxide,

each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, (carboxamido)alkyl, (cycloalkyl)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, aralkyl, —N(H)C(═O)R⁶, —C(═O)R⁷, and —S(═O)₂R⁸;

Y is selected from the group consisting of —C(R^(5a))(R^(5b))C(═O)—, —C(═O)—, and —S(═O)₂—;

B is selected from the group consisting of C₁₋₁₀ alkylenyl, optionally substituted C₃₋₁₂ cycloalkylenyl, optionally substituted C₆₋₁₄ arylenyl, optionally substituted 4- to 14-membered heterocyclenyl, and —C(H)R¹R²,

with the proviso that B is not optionally substituted pyrrolidinenyl;

X is selected from the group consisting of —N(R³)—, —S(═O)₂—, —S(═O)₂N(R³)—, —N(R³)S(═O)₂—, —S(═O)₂C(R⁴)(H)—, —C(═O)—, —C(═O)N(R³)—, —N(R³)C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R⁴)(H)N(R³)—, —N(R³)C(═O)C(R⁴)(H)—, and —C(═O)C(R⁴)(H)—; or X is absent, i.e., Z forms a bond with B;

Z is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl; or

Z is —CH(R^(9a))(R^(9b));

R^(9a) is selected from the group consisting of hydrogen, C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl;

R^(9b) is selected from the group consisting of optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl;

R¹ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl;

R² is selected from the group consisting of C₁₋₆ alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and (heteroaryl)alkyl;

R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl.

R^(5a) is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

R^(5b) is selected from the group consisting of hydrogen, C₁₋₄ alkyl, and 4- to 14-membered heterocyclo;

R⁶ is C₁₋₄ alkyl,

R⁷ is C₁₋₄ alkyl; and

R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino, alkylamino, and dialkylamino,

wherein —X—Z is attached to any available carbon or nitrogen atom of B, R¹, or R², e.g., when R² is C₁₋₆ alkyl, e.g., ethyl, a hydrogen atom of that ethyl group is replaced with —X—Z to give —CH₂CH₂—X—Z or

or

when R² is optionally substituted C₃₋₁₂ cycloalkyl, e.g., cyclohexyl, a hydrogen atom of the cyclohexyl group is replaced with —X—Z to give:

or

when R² is optionally substituted 4- to 14-membered heterocyclo, e.g., piperidinyl, the hydrogen atom attached to the piperidinyl nitrogen atom is replaced with —X—Z to give:

or

when R² is optionally substituted C₆₋₁₄ aryl, e.g., phenyl, a hydrogen atom on that phenyl group is replaced with —X—Z to give:

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent; B is optionally substituted 4- or 6- to 14-membered heterocyclenyl; and Z is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is optionally substituted 4- or 6- to 14-membered heterocyclenyl; X is absent; and Z is —CH(R^(9a))(R^(9b)).

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is optionally substituted 4- or 6- to 14-membered heterocyclenyl; X is absent; and Z is —CH(R^(9a))(R^(9b)), wherein:

R^(9a) is selected from the group consisting of hydrogen, C₁₋₆ alkyl, and optionally substituted C₃₋₁₂ cycloalkyl; and

R^(9b) is selected from the group consisting of optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is C₁₋₁₀ alkylenyl. In another embodiment, X is selected from the group consisting of —N(R³)C(═O)C(R⁴)(H)— and —N(R³)C(═O)—. In another embodiment, Z is selected from the group consisting of C₁₋₆ alkyl and (amino)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is optionally substituted C₆₋₁₄ arylenyl. In another embodiment, B is divalent form of optionally substituted phenyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula II:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent and Z is (amino)alkyl; and A and Y are as defined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is optionally substituted C₃₋₁₂ cycloalkylenyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula III, Formula IV, or Formula V:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R^(10a), R^(10b), R^(11a), and R^(11b) are each independently selected from the group consisting of hydrogen and C₁₋₄ alkyl; and A, Y, X, and Z are as defined above in connection with Formula I. In another embodiment, X is —N(R³)C(═O)— and Z is (amino)alkyl. In another embodiment, X is —N(R³)— and Z is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is optionally substituted 4- to 14-membered heterocyclenyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula VI, Formula VII, or Formula VIII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R^(12a), R^(12b), R^(13a), and R^(13b) are each independently selected from the group consisting of hydrogen and C₁₋₄ alkyl; and A, Y, X, and Z are as defined above in connection with Formula I. In another embodiment, X is selected from the group consisting of —C(═O)C(R⁴)(H)—, —C(═O)—, and —S(═O)₂—; and R⁴ is selected from the group consisting of hydrogen and amino. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and (hetaroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula VI, Formula VII, or Formula VIII, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R^(12a), R^(12b), R^(13a), and R^(13b) are each independently selected from the group consisting of hydrogen and C₁₋₄ alkyl; A is 5-indolinyl-2-one that is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, and hydroxyalkyl; Y is —C(═O)—; X is —S(═O)₂—; and Z is as defined above in connection with Formula I. In another embodiment, A is 6-chloro-5-indolinyl-2-one, i.e.,

In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and (hetaroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is —C(H)R¹R². In this embodiment, a hydrogen atom of R¹ and R² is replaced with —X—Z.

In another embodiment, Compounds of the Disclosure are compounds having Formula IX, Formula X, or Formula XI:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof. In another embodiment, R¹ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, alkoxycarbonyl, and optionally substituted C₆₋₁₄ aryl. In another embodiment, R¹ is selected from the group consisting of hydrogen and methyl. In another embodiment, X is —C(═O)C(R⁴)(H)— and R⁴ is amino. In another embodiment, X is selected from the group consisting of:

In another embodiment, Z is C₁₋₆ alkyl. In another embodiment, Z is methyl.

In another embodiment, Compounds of the Disclosure are compounds having any one of Formula I-XI, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Y is —C(R^(5a))(R^(5b))C(═O)—. In another embodiment, R^(5a) and R^(5b) are each independently selected from the group consisting of hydrogen and methyl.

In another embodiment, Compounds of the Disclosure are compounds having any one of Formula I-XI, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Y is —S(═O)₂—.

In another embodiment, Compounds of the Disclosure are compounds having any one of Formula I-XI, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Y is —C(═O)—.

In another embodiment, Compounds of the Disclosure are compounds having any one of Formula I-XI, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is selected from the group consisting of 1,2,3-triazolyl, 1,2,4-triazolyl, 2-(1,2,3,4-tetrahydroquinolinyl), 2-indolyl, 2-thiazolyl, 3-(1,2,4-oxadiazolyl), 3-isothiazolyl, 5-(1,3-dihydro-2H-benzo[d]imidazolyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-b]pyridinyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-c]pyridinyl-2-one), 5-(2,2-difluorobenzo[d][1,3]dioxolyl), 5-benzo[d]oxazolyl-2(3H)-one, 5-indolinyl-2-one, 6-benzo[b][1,4]oxazinyl-3-one, and 6-isoquinolinyl.

In another embodiment, Compounds of the Disclosure are compounds having any one of Formula I-XI, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is 5-indolinyl-2-one.

In another embodiment, Compounds of the Disclosure are compounds having Formula XII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:

A¹ is selected from the group consisting of 1,2,3-triazolyl, 1,2,4-triazolyl, 1-imidazolyl, 1-isoquinolinyl, 1-pyrazolyl, 2-(1,2,3,4-tetrahydroquinolinyl), 2-benzo[d]imidazolyl, 2-benzo[d]thiazolyl, 2-chromenyl-4-one, 2-furanyl, 2-imidazo[1,2-b]pyridazinyl, 2-imidazolyl, 2-indolyl, 2-naphthalenyl, 2-pyrazinyl, 2-pyridyl, 2-pyrimidinyl, 2-pyrrolidinyl, 2-pyrrolyl, 2-quinolinyl, 2-quinoxalinyl, 2-thiazolo[5,4-c]pyridinyl, 2-thiazolyl, 2-thiophenyl, 3-(1,2,3,4-tetrahydroisoquinoline), 3-(1,2,4-oxadiazolyl), 3-imidazo[1,2-a]pyrimidinyl, 3-indazolyl, 3-indolyl, 3-isothiazolyl, 3-pyrazolyl, 3-pyridazinyl, 3-pyridinyl-2-one, 3-pyridyl, 3-pyrrolo[3,2-b]pyridinyl, 3-quinolinyl, 4-(2,2-difluorobenzo[d][1,3]dioxolyl), 4-cyclohexanyl-1-amine, 4-imidazolyl, 4-indolinyl-2-one, 4-indolyl, 4-isothiazolyl, 4-oxazolyl, 4-piperidinyl, 4-pyrazolyl, 4-pyridyl, 4-quinolinyl, 5-(1,3-dihydro-2H-benzo[d]imidazolyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-b]pyridinyl-2-one), 5-(1,3-dihydro-2H-pyrrolo[2,3-c]pyridinyl-2-one), 5-(2,2-difluorobenzo[d][1,3]dioxolyl), 5-(2,4-dihydro-3H-1,2,4-triazolyl-3-one), 5-4H-furo[3,2-b]pyrrolyl, 5-benzo[c][1,2,5]oxadiazolyl, 5-benzo[d][1,3]dioxolyl, 5-benzo[d]oxazolyl-2(3H)-one, 5-bicyclo[2.2.1]heptyl-2-ene, 5-indolinyl-2,3-dione, 5-indolinyl-2-one, 5-indolyl, 5-isoindolinyl-1-one, 5-isoxazolyl, 5-pyrazolo[3,4-c]pyridinyl, 5-pyrazolyl, 5-pyrimidinyl, 5-thiazolyl, 6-(1,2,3,4-tetrahydronaphthalenyl), 6-(3,4-dihydroquinolinyl-2(1H)-one), 6-(3,4-dihydroquinoxalinyl-2(1H)-one), 6-(4,5-dihydropyridazinyl-3 (2H)-one), 6-benzo[b][1,4]oxazinyl-3-one, 6-benzo[d]imidazolyl, 6-benzo[d]oxazolyl-2(3H)-one, 6-benzo[d]thiazolyl, 6-chromenyl-2-one, 6-imidazo[2,1-b]thiazole, 6-indazolyl, 6-indolinyl-2-one, 6-indolyl, 6-isoquinolinyl, 6-quinolinyl, 6-quinoxalinyl, 6-quinoxalinyl-2(1H)-one, 7-(3,4-dihydroquinolinyl-2(1H)-one), 7-(3,4-dihydroquinoxalin-2(1H)-one), 7-benzo[b][1,4]oxazinyl-3-one, 7-indolinyl-2-one, 7-quinolinyl, 8-benzo[b][1,4]oxazinyl-3-one, cyclopropanyl, phenyl, 4-(prop-1-en-1-yl)-imidazole, 1-butanyl-imidazole, sec-butylcyclopropane, 2-(ethylsulfonyl)propanyl, 1-isobutylpyrrolidine, 4-pyridyl 1-oxide, and 5-benzo[c][1,2,5]oxadiazolyl 1-oxide,

each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, (carboxamido)alkyl, (cycloalkyl)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and aralkyl;

B¹ is selected from the group consisting of optionally substituted C₃₋₁₂ cycloalkylenyl and optionally substituted 4- to 14-membered heterocyclenyl;

X¹ is selected from the group consisting of —N(R^(3a))—, —S(═O)₂—, —S(═O)₂N(R^(3a))—, —N(R^(3a))S(═O)₂—, —S(═O)₂C(R^(4a))(H)—, —C(═O)—, —C(═O)N(R^(3a))—, —N(R^(3a))C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R^(4a))(H)N(R^(3a))—, —N(R^(3a))C(═O)C(R^(4a))(H)—, and —C(═O)C(R^(4a))(H)—; or X¹ is absent, i.e., Z¹ forms a bond with B¹;

Z¹ is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl;

R^(3a) is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

R^(4a) is selected from the group consisting of hydrogen, C₁₋₄ alkyl, hydroxy, amino, alkylamino, and dialkylamino.

In another embodiment, Compounds of the Disclosure are compounds having Formula XII, or a pharmaceutically acceptable salt or hydrate thereof, wherein A¹ is 5-indolinyl-2-one. In another embodiment, B¹ is optionally substituted C₃₋₁₂ cycloalkylenyl. In another embodiment, X¹ is selected from the group consisting of —S(═O)₂— and —C(═O)—. In another embodiment, Z¹ is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, and (dialkylamino)alkyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula XIII:

or a pharmaceutically acceptable salt or hydrate thereof, wherein

X² is selected from the group consisting of —N(R^(3b))—, —S(═O)₂—, —S(═O)₂N(R^(3b))—, —N(R^(3b))S(═O)₂—, —S(═O)₂C(R^(4b))(H)—, —C(═O)—, —C(═O)N(R^(3b))—, —N(R^(3b))C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R^(4b))(H)N(R^(3b))—, —N(R^(3b))C(═O)C(R^(4b))(H)—, and —C(═O)C(R^(4b))(H)—; or X is absent, i.e., Z² forms a bond with the nitrogen atom;

Z² is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl;

R^(1a) is selected from the group consisting of hydrogen, C₁₋₆ alkyl, and optionally substituted C₆₋₁₄ aryl;

R^(3b) is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

R^(4b) is selected from the group consisting of hydrogen, C₁₋₄ alkyl, hydroxy, amino, alkylamino, and dialkylamino.

In another embodiment, Compounds of the Disclosure are compounds having Formula XIII, or a pharmaceutically acceptable salt or hydrate thereof, wherein X² is selected from the group consisting of —S(═O)₂— and —C(═O)—. In another embodiment, Z² is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, and (dialkylamino)alkyl. In another embodiment, X² is absent; and Z² is hydrogen. In another embodiment, R^(1a) is selected from the group consisting of hydrogen and methyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Y is —C(═O)— and A is selected from the group consisting of 5-indolinyl-2-one and 1,2,3-triazolyl.

In another embodiment, Compounds of the Disclosure are compounds having Formula XIV:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A, X, and Z are as defined above in connection with Formula I. In another embodiment, X is selected from the group consisting of S(═O)₂— and —S(═O)₂C(R⁴)(H)—. In another embodiment, X is —S(═O)₂—. In another embodiment, X is —S(═O)₂CH₂—. In another embodiment, Z is selected from the group consisting of optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C₃₋₁₂ cycloalkyl. In another embodiment, Z is optionally substituted 4- to 14-membered heterocyclo. In another embodiment, Z is an optionally substituted piperidinyl, wherein the nitrogen atom is attached to X or the 4-carbon atom is attached to X. In another embodiment, A is 5-indolinyl-2-one that is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, and hydroxyalkyl. In another embodiment, A is 6-chloro-5-indolinyl-2-one, i.e.,

In another embodiment, a Compound of the Disclosure is N-((1R,3r,5S)-8-((4-(benzylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide or 6-chloro-2-oxo-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.

It will be understood by those of ordinary skill in the art that compounds having Formula XIV can be drawn in various ways, e.g.,

In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is 1,2,3-triazolyl which may be optionally substituted with one substituent, and Y is —C(═O)—.

In another embodiment, Compounds of the Disclosure are compounds having having Formula XV:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:

R is selected from the group consisting of C₁₋₆ alkyl and C₃₋₁₂ cycloalkyl;

B is optionally substituted 4- or 6- to 14-membered heterocyclenyl, e.g., B is:

(wherein the nitrogen atom is attached to —X—Z); and

X and Z are as defined above in connection with Formula I. In another embodiment, X is absent. In another embodiment, Z is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl, or Z is —CH(R^(9a))(R^(9b)). In another embodiment, Z is selected from the group consisting of aralkyl and (heteroaryl)alkyl. In another embodiment, Z is (heteroaryl)alkyl that is substituted with an aralkyl, e.g.,

or (heteroaryl)alkyl, e.g.,

In another embodiment, Compounds of the Disclosure are compounds having having Formula XVI:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:

R″ is selected from the group consisting of C₁₋₆ alkyl and C₃₋₁₂ cycloalkyl;

B is optionally substituted 4- or 6- to 14-membered heterocyclenyl, e.g., B is:

(wherein the nitrogen atom is attached to —X—Z); and

X and Z are as defined above in connection with Formula I. In another embodiment, X is absent. In another embodiment, Z is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl, or Z is —CH(R^(9a))(R^(9b)). In another embodiment, Z is selected from the group consisting of aralkyl and (heteroaryl)alkyl. In another embodiment, Z is (heteroaryl)alkyl that is substituted with an aralkyl, e.g.,

or (heteroaryl)alkyl, e.g.,

In another embodiment, Compounds of the Disclosure are compounds having having Formula XVII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A, X, and Z are as defined above in connection with Formula I. In another embodiment, X is absent. In another embodiment, Z is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, aralkyl, and (heteroaryl)alkyl, or Z is —CH(R^(9a))(R^(9b)). In another embodiment, Z is selected from the group consisting of aralkyl and (heteroaryl)alkyl. In another embodiment, Z is aralkyl. In another embodiment, Z is (heteroaryl)alkyl. In another embodiment, Z is (heteroaryl)alkyl that is substituted with an aralkyl, e.g.,

or (heteroaryl)alkyl, e.g.,

In another embodiment, Compounds of the Disclosure are compounds having having Formula XVIII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:

R′″ is selected from the group consisting of aralkyl and (heteroaryl)alkyl; and

A is as defined above in connection with Formula I. In another embodiment, A is selected from the group consisting of 1,2,3-triazolyl, 3-pyridazinyl, 2-pyridyl, and 2-imidazolyl, each of which is optionally substituted with one substituent selected from the group consisting of C₁₋₆ alkyl and C₃₋₆ cycloalkyl. In another embodiment, A is selected from the group consisting of:

In another embodiment, R′″ is aralkyl. In another embodiment, R′″ is (heteroaryl)alkyl. In another embodiment, R′″ is benzyl wherein the phenyl group is optionally substituted with one or two substituents, e.g., —CH₂(4-Cl-Ph), —CH₂(3-Cl-Ph), and —CH₂(4-CF₃-Ph).

In another embodiment, Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 1 are provided in Table 1A.

In another embodiment, Compounds of the Disclosure are compounds of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 3 are provided in Table 3A.

In another embodiment, Compounds of the Disclosure are compounds of Table 4, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 4 are provided in Table 4A.

In another embodiment, Compounds of the Disclosure are compounds of Table 5, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.

In another embodiment, Compounds of the Disclosure are compounds of Table 6, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 6 are provided in Table 6A.

In another embodiment, Compounds of the Disclosure are compounds of Tables 1, 1A, 3, 3A, 4, 4A, 5, 6 and 6A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.

In another embodiment, Compounds of the Disclosure are compounds selected from the group consisting of:

-   rel-N-{1-[(1S)-1-[2-chloro-3-(2-hydroxyethoxy)phenyl]ethyl]azetidin-3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide; -   N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylpyridazine-3-carboxamide; -   N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropylpicolinamide; -   N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide; -   N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide;     and -   1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4-carboxamide,

and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.

It should be appreciated that the Compounds of the Disclosure in certain embodiments are the free base, various salts, and hydrate forms, and are not limited to the particular salt listed in Tables 1 and 3-6.

TABLE 1 Cpd. Salt No. Structure Form 3

None 4

None 5

None 6

None 7

8

None 9

None 10

None 11

HCl 12

None 13

HCl 14

HCl 15

HCl 16

HCl 17

HCl 18

TFA 19

TFA 20

TFA 21

TFA 22

TFA 23

HCl 24

HCl 25

HCl 26

HCl 27

HCl 28

HCl 29

HCl 30

HCl 31

HCl 32

HCl 33

HCl 34

HCl 35

HCl 36

HCl 37

HCl 38

None 39

None 40

HCl 42

HCl 43

HCl 44

TFA 45

TFA 46

TFA 47

HCl 48

HCl 49

HCl 50

HCl 51

TFA 52

HCl 53

HCl 54

HCl 55

HCl 56

HCl 57

HCl 58

HCl 59

HCl 60

HCl 61

HCl 62

HCl 63

HCl 64

HCl 65

HCl 66

HCl 67

HCl 68

HCl 69

TFA 70

TFA 71

TFA 72

TFA 73

HCl 74

HCl 75

HCl 76

HCl 77

HCl 78

HCl 79

HCl 80

HCl 81

TFA 82

TFA 83

TFA 84

TFA 85

HCl 86

HCl 87

HCl 88

TFA 89

TFA 90

TFA 91

TFA 92

TFA 93

HCl 94

HCl 95

HCl 96

HCl 97

HCl 98

HCl 99

TFA 100

HCl 101

HCl 102

HCl 103

TFA 104

TFA 105

TFA 106

TFA 107

TFA 108

HCl 109

HCl 110

HCl 111

HCl 112

TFA 113

HCl 114

TFA 115

TFA 116

TFA 117

TFA 118

TFA 119

HCl 120

TFA 121

HCOOH 122

TFA 123

TFA 125

TFA 126

TFA 127

TFA 129

TFA 130

TFA 131

HCOOH 132

TFA 133

TFA 134

TFA 135

TFA 136

HCl 137

HCl 138

HCl 139

HCl 140

HCl 141

HCl 142

HCl 143

HCl 144

HCl 145

HCl 146

HCl 147

HCl 148

HCl 149

HCl 150

HCl 151

HCl 152

HCl 153

HCl 154

HCl 155

HCl 156

HCl 157

HCl 158

HCl 159

HCl 160

HCl 161

HCl 162

HCl 163

HCl 164

HCl 165

HCl 166

HCl 167

HCl 168

HCl 169

TFA 170

TFA 171

TFA 172

TFA 173

TFA 174

TFA 175

TFA 176

HCOOH 177

TFA 178

TFA 179

HCl 180

HCl 181

None 182

None 183

None 184

HCl 185

TFA 186

TFA 187

HCl 188

HCl 189

HCl 190

HCl 191

HCl 192

HCl 193

HCl 194

HCl 195

HCl 196

TFA 197

TFA 198

TFA 199

HCl 200

TFA 201

TFA 202

HCl 203

HCl 204

HCl 205

HCl 206

HCl 207

HCl 208

TFA 209

HCl 210

HCl 211

TFA 212

TFA 213

TFA 214

TFA 215

HCl 216

TFA 217

TFA 218

TFA 219

TFA 220

TFA 221

TFA 222

TFA 223

TFA 224

TFA 225

TFA 226

TFA 227

TFA 228

TFA 229

HCl 230

HCl 231

HCl 232

HCl 233

HCl 234

HCl 235

HCl 236

TFA 237

TFA 238

TFA 239

TFA 241

TFA 242

None 243

TFA 244

HCl 245

HCl 246

HCl 247

TFA 248

None 249

TFA 250

TFA 251

HCl 252

HCl 253

TFA 254

TFA 255

TFA 256

TFA 257

TFA 258

TFA 259

TFA 260

TFA 261

TFA 262

HCl 263

TFA 264

HCl 265

TFA 266

TFA 267

TFA 268

TFA 269

HCl 270

HCl 271

HCl 272

HCl 273

TFA 274

TFA 275

TFA 276

TFA 277

TFA 278

TFA 279

TFA 280

TFA 281

HCl 283

HCl 284

TFA 285

HCl 286

TFA 287

TFA 288

None 289

None 290

None 291

None 292

None 293

None 294

HCl 295

TFA 296

HCl 297

HCl 298

HCl 299

TFA 300

TFA 301

TFA 302

TFA 303

HCl 304

HCl 305

TFA 306

TFA 307

TFA 308

HCl 309

TFA 310

TFA 311

TFA 312

TFA 313

TFA 314

TFA 315

TFA 316

TFA 317

HCl 318

HCl 319

TFA 320

None 321

HCl 322

None 323

TFA 324

TFA 325

HCl 326

HCl 327

HCl 328

None 329

HCl 330

HCl 331

HCl 332

HCl 333

None 334

None 335

None 336

None 337

None 338

TFA 339

None 340

HCl 341

TFA 342

TFA 343

TFA 344

HCl 345

HCl 346

HCl 347

HCl 348

TFA 349

TFA 350

TFA 351

HCl 352

HCl 353

HCl 354

HCl 355

HCl 356

HCl 357

None 358

TFA 359

TFA 360

None 361

TFA 362

TFA 363

TFA 364

TFA 365

TFA 366

TFA 367

TFA 368

HCl 369

HCl 370

TFA 371

TFA 372

TFA 373

TFA 374

TFA 375

TFA 376

TFA 378

HCl 379

TFA 380

None 381

TFA 382

TFA 383

TFA 384

TFA 385

TFA 386

TFA 387

TFA 388

None 389

TFA 390

HCl 391

TFA 392

TFA 393

TFA 394

None 395

HCl 396

TFA 397

TFA 398

TFA 399

HCl 400

HCl 401

TFA 402

TFA 403

TFA 404

None 405

None 406

TFA 407

TFA 408

TFA 409

HCl 410

HCl 411

HCl 412

TFA 413

TFA 414

TFA 415

TFA 416

TFA 417

TFA 418

TFA 419

TFA 420

TFA 421

TFA 422

TFA 423

TFA 424

TFA 425

TFA 426

TFA 427

TFA 428

TFA 429

TFA 430

HCl 431

TFA 432

TFA 433

HCl 434

HCl 435

HCl 436

TFA 437

None 438

TFA 439

HCl 440

HCl 441

TFA 442

HCl 443

HCl 444

TFA 445

TFA 446

TFA 447

TFA 448

TFA 449

TFA 450

None 451

TFA 452

TFA 453

TFA 454

TFA 455

None 456

TFA 457

TFA 458

None 459

TFA 460

TFA 461

TFA 462

TFA 463

TFA 464

HCl 465

TFA 466

TFA 467

TFA 468

TFA 469

TFA 470

TFA 471

HCl 472

None 473

TFA 474

TFA 475

TFA 476

TFA 477

TFA 478

TFA 479

TFA 480

TFA 481

TFA 482

TFA 483

TFA 484

None 485

None 486

TFA 487

TFA 488

TFA 489

TFA 490

TFA 491

TFA 492

None 493

TFA 494

None 495

None 496

TFA 497

TFA 498

TFA 499

TFA 500

TFA 501

TFA 502

TFA 503

TFA 504

TFA 505

TFA 506

TFA 507

TFA 508

TFA 509

TFA 510

TFA 511

HCl 512

TFA 513

None 514

None 515

TFA 516

None 517

None 518

None 519

TFA 520

TFA 521

None 522

None 523

HCl 525

HCl 527

TFA 528

TFA 529

TFA 530

TFA 531

TFA 532

TFA 533

TFA 534

None 535

None 536

None 537

None 538

TFA 539

None 540

TFA 541

TFA 541

None 543

TFA 544

TFA 545

TFA 546

TFA 547

None 548

TFA 549

TFA 550

TFA 551

TFA 552

TFA 553

TFA 554

TFA 555

TFA 556

TFA 557

HCl 558

HCl 559

HCl 560

TFA 561

TFA 562

TFA 563

HCl 564

HCl 565

TFA 566

TFA 567

HCl 568

HCl 569

HCl 570

HCl 571

HCl 572

TFA 573

HCl 574

TFA

TABLE 3 Cpd. Salt No. Structure Form 575

TFA 576

None 577

TFA 578

TFA 579

HCl 580

None 581

None 582

HCl 583

TFA 584

TFA 585

TFA 586

HCl 587

TFA 588

TFA 589

HCl 590

None 591

TFA 592

TFA 593

None 594

None 595

None 596

TFA 597

HCl 598

TFA 599

TFA 600

TFA 601

HCl 602

None 603

TFA 604

TFA 605

HCl 606

None 607

HCl 608

TFA 609

HCl 610

HCl 611

TFA 612

TFA 613

TFA 614

None 615

None 616

TFA 617

TFA 618

HCl 619

TFA 620

TFA 621

TFA 622

TFA 623

None 624

None 625

HCl 626

HCl 627

HCl 628

HCl 629

None 630

None 631

HCl 632

None 633

None 634

None 635

HCl 636

HCl 637

None 638

TFA 639

None 640

TFA 641

None 642

HCl 643

None 644

HCl

TABLE 4 Cpd. Salt No. Structure Form 645

None 646

None 647

None 648

None 649

None 650

None 651

None 652

None 657

None 659

None 660

None 661

None 662

None 663

None 664

None 665

None 666

None 667

None 668

None 669

None 670

None 671

None 672

None 673

None 674

None 675

None 676

None 677

None 678

None 679

None 680

None 681

None 682

None 683

None 684

None 685

None 686

None 687

None 688

None 689

None 690

None 691

None 692

None 693

None 694

None 695

None 696

None 697

None 698

None 699

None 700

None 701

None 702

None 703

None 704

None 705

None 706

None 707

None 708

None 709

None 710

None 711

None 712

None 713

None 714

None 715

None 716

None 717

None 718

None 719

None 720

None 721

None 722

None 723

None 724

None 725

None 726

None 727

None 728

None 729

None 730

None 731

None 732

None 733

None 734

None 735

None 736

None 737

None 738

None 739

None 740

None 741

None 742

None 743

None 744

None 745

None 746

None 747

None 748

None 749

None 750

None 751

None 752

None 753

None 754

None 755

None 756

None 757

None 758

None 759

None 760

None 761

None 762

None 763

None 764

None 765

None 766

None 767

None 768

None 769

None 770

None 771

None 772

None 773

None 774

None 775

None 776

None 777

None 778

None 779

None 780

None 781

None 782

None 783

None 784

None 785

None 786

None 787

None 788

None 789

None 790

None 791

None 792

None 793

None 794

None 795

None 796

None 797

None 798

None 799

None 800

None 801

None 802

None 803

None 804

None 805

None 806

None 807

None 808

None 809

None 810

None 811

None 812

None 813

None 814

None 815

None 816

None 817

None 818

None 819

None 820

None 821

None 822

None 823

None 824

None 825

None 826

None 827

None 828

None 829

None 830

None 831

None 832

None 833

None 834

None 835

None 836

None 837

None 838

None 839

None 840

None 841

None 842

None 843

None 844

None 845

None 846

None 847

None 848

None 849

None 850

None 851

None 852

None 853

None 854

None 855

None 856

None 857

None 858

None 859

None 860

None 861

None 862

None 863

None 864

None 865

None 866

None 867

None 868

None 869

None 913

None 914

None 915

None 916

None 917

None 918

None

TABLE 5 Cpd. No. Structure Chemical Name 870

(R)-1-cyclopropyl-N-(1-(1- (2- methoxyphenyl)ethyl)azetidin- 3-yl)-1H-1,2,3-triazole-4- carboxamide 871

1-cyclopropyl-N-(1-(5- methoxy-1,2,3,4- tetrahydronaphthalen-1- yl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 872

1-cyclopropyl-N-(1-(1- methylpiperidin-2-yl)ethyl)- 1H-1,2,3-triazole-4- carboxamide 873

5-cyclopropyl-N-(1-(1- methylpiperidin-2- yl)ethyl)pyridazine-3- carboxamide 874

N-(1-(2-(4- (benzyloxy)phenyl)propan-2- yl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 875

N-(1-(1-(4- (benzyloxy)phenyl) cyclopropyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 876

1-cyclopropyl-N-(1-(4-(1- hydroxy-2- phenylethyl)benzyl(azetidin- 3-yl)-1H-1,2,3-triazole-4- carboxamide 877

1-cyclopropyl-N-(1-(4- (pyridin-3- ylmethoxy)benzyl)azetidin- 3-yl)-1H-1,2,3-triazole-4- carboxamide 878

N-(1-(4-((1,3,4-thiadiazol-2- yl)methoxy)benzyl)azetidin- 3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 879

1-cyclopropyl-N-(1- isopropylazetidin-3-yl)-1H- imidazole-4-carboxamide 880

1-cyclopropyl-N-(3- (dimethylamino)propyl)-1H- 1,2,3-triazole-4-carboxamide 881

N-(1-(1-(4-(benzyloxy)-3- methoxyphenyl)ethyl)azetidin- 3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 882

N-(1-1-(3-(2-chlorophenyl)- 1H-indazol-5- yl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 883

1-cyclopropyl-N-(1-(1-(5- methoxypyridin-2- yl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 884

1-cyclopropyl-N-(1-(1-(2- methyl-2H-indazol-5- yl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 885

5-cyclopropyl-N-(1-(1-(3- methoxyphenyl)ethyl)azetidin- 3-yl)pyridazine-3- carboxamide 886

N-(1-(1-(5-chloro-2- (difluoromethoxy)phenyl) ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 887

1-cyclopropyl-N-(1-(1-(4- (phenoxymethyl)phenyl) ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 888

N-(1-(1-(3-(2-aminoethoxy)- 2-chlorophenyl)ethyl)azetidin- 3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 889

N-(1-(1-(2-chloro-3-(2- (methylamino)ethoxy)phenyl) ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 890

N-(1-(1-(2-chloro-3-(2- (dimethylamino)ethoxy) phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 891

N-(1-(1-(2-chloro-3-(2- hydroxypropoxy)phenyl) ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 892

N-(1-(1-(2-chloro-3-(2- hydroxy-2- methylpropoxy)phenyl)ethyl) azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4- carboxamide 893

N-(1-(1-(2-chloro-3-(2,3- dihydroxypropoxy)phenyl) ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 894

N-(1-(1-(2-chloro-5- methoxyphenyl)ethyl)azetidin- 3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 895

N-(1-(1-(5-chloro-2- (trifluoromethyl)phenyl)ethyl) azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 896

1-cyclopropyl-N-(1-(1-(4- ((4- methylbenzyl)oxy)phenyl) ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 897

N-(1-(bicyclo[2.2.2]octan-1- ylmethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 898

1-cyclopropyl-N-(1-((4- methoxybicyclo[2.2.2]octan- 1-yl)methyl)azetidin-3-yl)- 1H-1,2,3-triazole-4- carboxamide 899

1-cyclopropyl-N-(2,2- dimethyl-1-(1- phenylethyl)azetidin-3-yl)- 1H-1,2,3-triazole-4- carboxamide 900

1-cyclopropyl-N-(1- (piperidin-2-yl)ethyl)-1H- 1,2,3-triazole-4-carboxamide 901

5-cyclopropyl-N-(1- (piperidin-2- yl)ethyl)pyridazine-3- carboxamide 902

5-cyclopropyl-N-(8-methyl- 8-azabicyclo[3.2.1]octan-3- yl)pyridazine-3-carboxamide 903

1-cyclopropyl-N-(1-(1-(4- (2,2,2- trifluoroethoxy)phenyl)ethyl) azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 904

1-cyclopropyl-N-(1-(1-(4- (piperidin-4- ylmethoxy)phenyl)ethyl) azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 905

1-cyclopropyl-N-(1-(1-(6- oxo-1,6-dihydropyridin-3- yl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 906

N-(1-(1-(5-chloro-2-(4- fluorophenoxy)phenyl)ethyl) azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4- carboxamide 907

N-(1-(1-(4-((4- acetamidobenzyl)oxy)phenyl) ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3- triazole-4-carboxamide 908

1-cyclopropyl-N-(1-(1-(4- ((phenylamino)methyl)phenyl) ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 909

1-cyclopropyl-N-(1-(2,2,2- trifluoro-1-(4- fluorophenyl)ethyl)azetidin- 3-yl)-1H-1,2,3-triazole-4- carboxamide 910

N-(1-(1-(4-chlorophenyl)- 2.2.2-trifluoroethyl)azetidin- 3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 911

1-cyclopropyl-N-(1-(2,2,2- trifluoro-1-(m- tolyl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 912

1-cyclopropyl-N-(1-(2,2,2- trifluoro-1-(3- fluorophenyl)ethyl)azetidin- 3-yl)-1H-1,2,3-triazole-4- carboxamide

TABLE 6 Cpd. Salt No. Structure Form 919

none 920

none 921

none 922

none 923

none 924

none 925

none 926

none 927

none 928

none 929

none 930

none 931

none 932

none 933

none 934

none 935

none 936

none 937

none 938

none 939

none 940

none 941

none 942

none 943

none 944

none 945

none 946

none 947

none 948

none 949

none 950

none 951

none 952

none 953

none 954

none 955

none 956

none 957

none 958

none 959

none 960

none 961

none 962

none 963

none 964

none 965

none 966

none 967

none 968

none 969

none 970

none 971

none 972

none 973

none 974

none 975

none 976

none 977

none 978

none 979

none 980

none 981

none 982

none 983

none 984

none 985

none 986

none 987

none 988

none 989

none 990

none 991

none 992

none 993

none 994

none 995

none 996

none 997

none 998

none 999

none 1000

none 1001

none 1002

none 1003

none 1004

none 1005

none 1006

none 1007

none 1008

none 1009

none 1012

none 1017

none 1020

none 1021

none 1022

none 1023

none 1024

none 1025

none 1026

none 1028

none

TABLE 1A SMYD3 SMYD3 Biochem Cell Cpd. LCMS IC₅₀ IC₅₀ No. Chemical Name M + H (μM)* (μM)* 3 N-(1-((4- 403.2 >100 acetamidophenyl)sulfonyl)piperidin-4- yl)nicotinamide 4 N-(1-((4- 403.2 >100 acetamidophenyl)sulfonyl)piperidin-4- yl)isonicotinamide 5 N-(1-((4- 404.2 >100 acetamidophenyl)sulfonyl)piperidin-4- yl)pyrazine-2-carboxamide 6 N-(1-((4- 392.3 >100 acetamidophenyl)sulfonyl)piperidin-4-yl)- 1H-pyrazole-3-carboxamide 7 N-(1-((4- 406.3 >100 acetamidophenyl)sulfonyl)piperidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamide 8 N-(1-((4- 406.3 >100 acetamidophenyl)sulfonyl)piperidin-4-yl)-1- methyl-1H-pyrazole-4-carboxamide 9 N-(1-((4- 406.3 60.5 acetamidophenyl)sulfonyl)piperidin-4-yl)-1- methyl-1H-imidazole-4-carboxamide 10 N-(1-((4- 433.2 16.98 acetamidophenyl)sulfonyl)piperidin-4-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 11 N-((1r,4r)-4-aminocyclohexyl)-1- 250 15.37 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 12 N-(1-((4- 463 45.94 acetamidophenyl)sulfonyl)piperidin-4-yl)-1- (cyclopropylmethyl)piperidine-4- carboxamide 13 N-((1r,4r)-4-aminocyclohexyl)-1-ethyl-1H- 237.1 112.37 pyrazole-3-carboxamide 14 N-((1r,4r)-4-aminocyclohexyl)-3- 238.15 104.43 ethylisoxazole-5-carboxamide 15 N-((1r,4r)-4-aminocyclohexyl)-1-ethyl-1H- 237.1 56.59 imidazole-4-carboxamide 16 N-((1r,4r)-4-aminocyclohexyl)-2- NA 128.43 ethyloxazole-4-carboxamide 17 N-((1r,4r)-4-aminocyclohexyl)-5- 254.1 13.52 ethylisothiazole-3-carboxamide 18 N-((1r,4r)-4-aminocyclohexyl)-4- 247.1 125.3 ethylbenzamide 19 N-((1r,4r)-4-aminocyclohexyl)-3-oxo-3,4- 289.9 102.25 dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 20 N-((1r,4r)-4-aminocyclohexyl)-3-oxo-3,4- 289.8 16.03 dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 21 N-((1r,4r)-4-aminocyclohexyl)-3- 247.3 57.46 ethylbenzamide 22 N-((1r,4r)-4-aminocyclohexyl)-5- 247.9 31.29 ethylnicotinamide 23 3-acetyl-N-((1r,4r)-4- 261.2 91.55 aminocyclohexyl)benzamide 24 3-acetamido-N-((1r,4r)-4- 276.2 80.28 aminocyclohexyl)benzamide 25 N-((1r,4r)-4-aminocyclohexyl)-3- 290.2 84.27 propionamidobenzamide 26 N-((1r,4r)-4-aminocyclohexyl)-3- 248.9 86.01 (hydroxymethyl)benzamide 27 N-((1r,4r)-4-aminocyclohexyl)-1-ethyl-3- 251.2 101.58 methyl-1H-pyrazole-5-carboxamide 28 N-((1r,4r)-4-aminocyclohexyl)-3-methyl-1- 299.25 110.89 phenyl-1H-pyrazole-5-carboxamide 29 N-((1r,4r)-4-aminocyclohexyl)-1-benzyl-3- 313.2 13.99 methyl-1H-pyrazole-5-carboxamide 30 1-ethyl-3-methyl-N-(phenyl(piperidin-4- 327.15 69.19 yl)methyl)-1H-pyrazole-5-carboxamide 31 3-methyl-1-phenyl-N-(phenyl(piperidin-4- 375.2 56.66 yl)methyl)-1H-pyrazole-5-carboxamide 32 1-benzyl-3-methyl-N-(phenyl(piperidin-4- 389.25 91.27 yl)methyl)-1H-pyrazole-5-carboxamide 33 N-(4-(aminomethyl)phenyl)-6- 228.05 130.63 hydroxypyridazine-3-carboxamide (−NH₂) 34 N-(4-(aminomethyl)phenyl)-1-methyl-3- 282.1 153.36 (trifluoromethyl)-1H-pyrazole-5- (−NH₂) carboxamide 35 N-(4-(aminomethyl)phenyl)-1-ethyl-3- 242.05 124.89 methyl-1H-pyrazole-5-carboxamide (−NH₂) 36 N-(4-(aminomethyl)phenyl)-3-methyl-1- 290.15 123.93 phenyl-1H-pyrazole-5-carboxamide (−NH₂) 37 N-((1r,4r)-4-aminocyclohexyl)-3-ethyl-1- 251.34 59.91 methyl-1H-pyrazole-5-carboxamide 38 N-((1r,4r)-4-aminocyclohexyl)-4- 248 20.5 ethylpicolinamide 39 2-oxo-N-(piperidin-4-yl)-1,2,3,4- 274.9 23.86 tetrahydroquinoxaline-6-carboxamide 40 N-((1r,4r)-4-aminocyclohexyl)-2- 274.1 2.84 oxoindoline-5-carboxamide 42 N-((1r,4r)-4-aminocyclohexyl)-2- 274.2 3.31 oxoindoline-5-carboxamide 43 N-((1r,4r)-4-aminocyclohexyl)-2- 287 60.36 hydroxyquinoxaline-6-carboxamide 44 2-oxo-N-(phenyl(piperidin-4- 350.25 14.08 yl)methyl)indoline-5-carboxamide 45 5-amino-N-(phenyl(piperidin-4-yl)methyl)- 300.25 137.24 1H-pyrazole-3-carboxamide 46 3-oxo-N-(piperidin-4-yl)-3,4- 272.9 63.74 dihydroquinoxaline-6-carboxamide 47 N-((1r,4r)-4-aminocyclohexyl)-2-oxo-2,3- 274.8 11.94 dihydro-1H-pyrrolo[2,3-b]pyridine-5- carboxamide 48 3-amino-N-((1r,4r)-4-aminocyclohexyl)-1- 237.9 117.12 methyl-1H-pyrazole-5-carboxamide 49 N-(1-(L-tyrosyl)piperidin-4-yl)-2- 423.3 0.86 oxoindoline-5-carboxamide 50 2-oxo-N-(piperidin-4-yl)indoline-5- 260.2 12.15 carboxamide 51 N-(1-(L-tryptophyl)piperidin-4-yl)-2- 446.4 0.69 oxoindoline-5-carboxamide 52 N-(4-(aminomethyl)phenyl)-4-propionyl-1H- 272.2 107.67 pyrrole-2-carboxamide 53 N-((1r,4r)-4-aminocyclohexyl)-2- 239.3 121.58 butylcyclopropane-1-carboxamide 54 N-((1r,4r)-4-aminocyclohexyl)-5- 253.4 49.88 ethylthiophene-2-carboxamide 55 5-ethyl-N-(phenyl(piperidin-4- 329.2 116.27 yl)methyl)thiophene-2-carboxamide 56 N-(4-(aminomethyl)phenyl)-5- 261.1 138.14 ethylthiophene-2-carboxamide 57 N-((1r,4r)-4-aminocyclohexyl)-2-methyl-4H- 261.7 134.08 furo[3,2-b]pyrrole-5-carboxamide 58 2-methyl-N-(piperidin-4-yl)-4H-furo[3,2- 248.1 76.14 b]pyrrole-5-carboxamide 59 N-((1r,4r)-4-aminocyclohexyl)-2- 254.5 184.11 ethylthiazole-5-carboxamide 60 2-ethyl-N-(phenyl(piperidin-4- 330.3 149.92 yl)methyl)thiazole-5-carboxamide 61 N-(4-(aminomethyl)phenyl)-2-ethylthiazole- 261.9 113.72 5-carboxamide 62 N-((1r,4r)-4-aminocyclohexyl)-3- 225.6 155.29 cyclopropylbutanamide 63 3-cyclopropyl-N-(phenyl(piperidin-4- 301.3 131.22 yl)methyl)butanamide 64 4-acetyl-N-((1r,4r)-4-aminocyclohexyl)-1H- 250.2 134.14 pyrrole-2-carboxamide 65 4-acetyl-N-(piperidin-4-yl)-1H-pyrrole-2- 236 45.83 carboxamide 66 4-acetyl-N-(4-(aminomethyl)phenyl)-1H- 258.2 60.87 pyrrole-2-carboxamide 67 N-((1r,4r)-4-ammocyclohexyl)-3-hydroxy-1- 238.8 129.1 methyl-1H-pyrazole-5-carboxamide 68 2-oxo-N-(piperidin-4-yl)-2,3-dihydro-1H- 261 86.06 pyrrolo[2,3-b]pyridine-5-carboxamide 69 3-hydroxy-1-methyl-N-(piperidin-4-yl)-1H- 225 19.72 pyrazole-5-carboxamide 70 N-((1r,4r)-4-aminocyclohexyl)-3-oxo- 289 77.47 1,2,3,4-tetrahydroquinoxaline-6-carboxamide 71 N-((1r,4r)-4-aminocyclohexyl)-2- 274.2 89.26 oxoindoline-6-carboxamide 72 N-(1-(L-tyrosyl)piperidin-4-yl)-2- 423.5 35.48 oxoindoline-6-carboxamide 73 N-((1r,4r)-4-aminocyclohexyl)-2-oxo-2,3- 275.1 13.7 dihydro-1H-benzo[d]imidazole-5- carboxamide 74 N-((1r,4r)-4-aminocyclohexyl)-2-oxo- NA 65.8 1,2,3,4-tetrahydroquinoline-6-carboxamide 75 6-amino-N-((1r,4r)-4-aminocyclohexyl)-2- 284.15 62.5 naphthamide 76 N-((1r,4r)-4-aminocyclohexyl)-2- 286.2 115.32 hydroxyquinoline-6-carboxamide 77 N-(phenyl(piperidin-4-yl)methyl)-4- 340.2 10.04 propionyl-1H-pyrrole-2-carboxamide 78 N-((1r,4r)-4-aminocyclohexyl)-2- 263.4 35.19 (ethylsulfonyl)propanamide 79 N-((1r,4r)-4-aminocyclohexyl)-5- 266 38.86 ((dimethylamino)methyl)furan-2- carboxamide 80 2-amino-N-(phenyl(piperidin-4- 301.4 97.11 yl)methyl)oxazole-4-carboxamide 81 N-(4-(aminomethyl)phenyl)-2-methyl-4H- 270.4 25.9 furo[3,2-b]pyrrole-5-carboxamide 82 N-(1-(L-tyrosyl)piperidin-4-yl)-1-methyl-2- 437.3 8.7 oxoindoline-5-carboxamide 83 N-(1-(L-tryptophyl)piperidin-4-yl)-1-methyl- 460.3 12.94 2-oxoindoline-5-carboxamide 84 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-2- 288.2 16.66 oxoindoline-5-carboxamide 85 N-((1r,4r)-4-aminocyclohexyl)-8-methoxy-3- NA 184.09 oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 86 N-(1-(1-(1-alanyl)piperidin-4-yl)ethyl)-2- 359.25 1.43 oxoindoline-5-carboxamide 87 N-(1-(1-(D-alanyl)piperidin-4-yl)ethyl)-2- 359.2 9.37 oxoindoline-5-carboxamide 88 N-(1-(L-tyrosyl)piperidin-4-yl)-1-methyl-2- 193.28 oxoindoline-6-carboxamide 89 N-((1r,4r)-4-aminocyclohexyl)-2-oxo-2,3- 258.89 140.17 dihydrobenzo[d]oxazole-5-carboxamide (−NH₂) 90 N-((1r,4r)-4-aminocyclohexyl)-2-oxo-2,3- 276.15 9.76 dihydrobenzo[d]oxazole-6-carboxamide 91 N-((1r,4r)-4-aminocyclohexyl)-2-oxo- 288.15 89.47 1,2,3,4-tetrahydroquinoline-7-carboxamide 92 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 373.2 49.95 oxo-1,2,3,4-tetrahydroquinoline-7- carboxamide 93 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 360.25 6.76 oxo-2,3-dihydro-1H-benzo[d]imidazole-5- carboxamide 94 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 361.25 3.94 oxo-2,3-dihydrobenzo[d]oxazole-6- carboxamide 95 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 372.3 149.61 oxo-2H-chromene-6-carboxamide 96 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 373.3 192.59 oxo-1,2,3,4-tetrahydroquinoline-6- carboxamide 97 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 369.3 145.77 amino-2-naphthamide 98 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-8- 405.25 150.97 methoxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 99 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 372.3 35.73 hydroxyquinoxaline-6-carboxamide 100 2-oxo-N-(piperidin-4-ylmethyl)indoline-5- 274.1 20.04 carboxamide 101 (S)-2-oxo-N-(pyrrolidin-3-ylmethyl)indoline- 260.1 25.36 5-carboxamide 102 N-((1-(L-tyrosyl)piperidin-4-yl)methyl)-2- 437.45 1.86 oxoindoline-5-carboxamide 103 N-((1-(L-tryptophyl)piperidin-4-yl)methyl)- 460.25 2.74 2-oxoindoline-5-carboxamide 104 ethyl 2-(1-(L-alanyl)piperidin-4-yl)-2-(2- 417.3 1.51 oxoindoline-5-carboxamido)acetate 105 N-((4-hydroxypiperidin-4-yl)methyl)-2- 290.2 40.39 oxoindoline-5-carboxamide 106 N-(4-aminobutyl)-2-oxoindoline-5- 248.2 13.42 carboxamide 107 (S)-N-(4-(2-aminopropanamido)butyl)-2- 319.3 13.95 oxoindoline-5-carboxamide 108 ethyl 5-(((1r,4r)-4-aminocyclohexyl)amino)- 257.3 92.19 5-oxopentanoate 109 2-methyl-N-(phenyl(piperidin-4-yl)methyl)- 330.5 79.04 3-(pyrrolidin-1-yl)propanamide 110 2-methyl-N-(phenyl(piperidin-4-yl)methyl)- 338.7 82.75 4H-furo[3,2-b]pyrrole-5-carboxamide 111 N-((1r,4r)-4-aminocyclohexyl)-2- 240.1 149.59 ethylpyrrolidine-2-carboxamide 112 N-((1-(L-alanyl)-4-hydroxypiperidin-4- 361.15 3.04 yl)methyl)-2-oxoindoline-5-carboxamide 113 N-((1-(L-alanyl)-4-fluoropiperidin-4- 363.25 3.86 yl)methyl)-2-oxoindoline-5-carboxamide 114 (R)-N-(4-(2-aminopropanamido)butyl)-2- 319.15 22.28 oxoindoline-5-carboxamide 115 N-((1r,4r)-4-aminocyclohexyl)-3-oxo-3,4- 290 61.18 dihydro-2H-benzo[b][1,4]oxazine-8- carboxamide 116 N-((1r,4r)-4-aminocyclohexyl)-5- 296.13/298.13 51 bromonicotinamide 117 N-((1r,4r)-4-aminocyclohexyl)-5- 254.2 86.99 chloronicotinamide 118 N-((1r,4r)-4- 276.2 139.34 aminocyclohexyl)benzo[d]thiazole-6- carboxamide 119 N-((1r,4r)-4-aminocyclohexyl)-2- 115.79 hydroxyquinoline-7-carboxamide 120 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 371.2 86.89 hydroxyquinoline-7-carboxamide 121 N-((4-methylpiperidin-4-yl)methyl)-2- 288.15 65.69 oxoindoline-5-carboxamide 122 ethyl 2-(2-oxoindoline-5-carboxamido)-2- 346.3 42.26 (piperidin-4-yl)acetate 123 6-amino-N-((1r,4r)-4- 235 107.83 aminocyclohexyl)nicotinamide 125 N-((1r,4r)-4-aminocyclohexyl)-7-fluoro-2- 304.7 91.68 hydroxyquinoline-4-carboxamide 126 N-((1r,4r)-4-aminocyclohexyl)-2-chloro-5- 320.1 31.99 (4H-1,2,4-triazol-4-yl)benzamide 127 N-((1r,4r)-4-aminocyclohexyl)-4H-1,2,4- 210.1 16.44 triazole-3-carboxamide 129 N-((1r,4r)-4-aminocyclohexyl)-2-(pyridin-3- 234.1 >100 yl)acetamide 130 N-(4-(3-aminopropanamido)cyclohexyl)-2- 345.1 0.29 oxoindoline-5-carboxamide 131 ethyl 4-((2-oxoindoline-5- 346.2 56.28 carboxamido)methyl)piperidine-4- carboxylate 132 ethyl 1-(L-alanyl)-4-((2-oxoindoline-5- 417.2 0.94 carboxamido)methyl)piperidine-4- carboxylate 133 N-(((S)-1-(D-alanyl)pyrrolidin-3-yl)methyl)- 331.15 10.67 2-oxoindoline-5-carboxamide 134 N-(((S)-1-(L-alanyl)pyrrolidin-3-yl)methyl)- 331.15 10.2 2-oxoindoline-5-carboxamide 135 N-(((R)-1-(L-alanyl)pyrrolidin-3-yl)methyl)- 331.1 13.62 2-oxoindoline-5-carboxamide 136 N-((1r,4r)-4-(3- 372.2 >100 aminopropanamido)cyclohexyl)-4-(5-methyl- 1,2,4-oxadiazol-3-yl)benzamide 137 N-((1r,4r)-4-aminocyclohexyl)-4-(5-methyl- 301.1 46.61 1,2,4-oxadiazol-3-yl)benzamide 138 N-(1-(1-(L-alanyl)piperidin-4- 305.2 >100 yl)ethyl)isonicotinamide 139 N-((1r,4r)-4-(3- 291.2 >100 aminopropanamido)cyclohexyl)isonicotinamide 140 N-((1r,4r)-4- 220.2 >100 aminocyclohexyl)isonicotinamide 141 N-(1-(1-(L-alanyl)piperidin-4- 305.2 >100 yl)ethyl)nicotinamide 142 N-((1r,4r)-4-(3- 291.2 >100 aminopropanamido)cyclohexyl)nicotinamide 143 N-((1r,4r)-4-aminocyclohexyl)nicotinamide 220.2 >100 144 N-(1-(1-(L-alanyl)piperidin-4- 306.2 >100 yl)ethyl)pyrimidine-2-carboxamide 145 N-((1r,4r)-4-(3- 292.2 >100 aminopropanamido)cyclohexyl)pyrimidine- 2-carboxamide 146 N-(1-(1-(L-alanyl)piperidin-4- 348.2 >100 yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide 147 N-((1r,4r)-4-(3- 334.2 98.15 aminopropanamido)cyclohexyl)benzo[d][1,3] dioxole-5-carboxamide 148 N-((1r,4r)-4- 263.1 >100 aminocyclohexyl)benzo[d][1,3]dioxole-5- carboxamide 149 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 382.2 >100 (methylsulfonyl)benzamide 150 N-((1r,4r)-4-(3- 368.2 >100 aminopropanamido)cyclohexyl)-3- (methylsulfonyl)benzamide 151 N-((1r,4r)-4-aminocyclohexyl)-3- 297.1 >100 (methylsulfonyl)benzamide 152 3-amino-N-((1r,4r)-4-(3- 307.2 >100 aminopropanamido)cyclohexyl)pyrazine-2- carboxamide 153 3-amino-N-((1r,4r)-4- 236.2 >100 aminocyclohexyl)pyrazine-2-carboxamide 154 N-((1r,4r)-4-(3- 366.1 37.31 aminopropanamido)cyclohexyl)-[1,1′- biphenyl]-4-carboxamide 155 N-((1r,4r)-4-aminocyclohexyl)-[1,1′- 295.1 79.21 biphenyl]-4-carboxamide 156 N-((1r,4r)-4-(3- 369.2 >100 aminopropanamido)cyclohexyl)-4- sulfamoylbenzamide 157 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 323.2 >100 fluoronicotinamide 158 N-((1r,4r)-4-(3- 309.2 >100 aminopropanamido)cyclohexyl)-5- fluoronicotinamide 159 N-((1r,4r)-4-aminocyclohexyl)-5- 238.2 >100 fluoronicotinamide 160 N-((1r,4r)-4-aminocyclohexyl)-1H-indole-6- 258.2 >100 carboxamide 161 N-((1r,4r)-4-aminocyclohexyl)-1H- 259.2 >100 benzo[d]imidazole-6-carboxamide 162 N-(1-(1-(L-alanyl)piperidin-4- 355.2 >100 yl)ethyl)quinoline-2-carboxamide 163 N-((1r,4r)-4-(3- 341.2 >100 aminopropanamido)cyclohexyl)quinoline-2- carboxamide 164 N-((1r,4r)-4-aminocyclohexyl)quinoline-2- 270.2 >100 carboxamide 165 N-((1r,4r)-4-(3- 341.2 15.52 aminopropanamido)cyclohexyl)isoquinoline- 6-carboxamide 166 N-((1r,4r)-4-aminocyclohexyl)isoquinoline- 270.2 20.7 6-carboxamide 167 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 357.3 >100 (1H-indol-3-yl)acetamide 168 N-((1r,4r)-4-aminocyclohexy l)-2-(1H-indol- 272.2 >100 3-yl)acetamide 169 3-amino-N-((1r,4r)-4-(2-(6- 398.3 >100 methoxynaphthalen-2- yl)propanamido)cyclohexyl)propanamide 170 N-((1r,4r)-4-aminocyclohexyl)-2-(6- 327.3 76.38 methoxynaphthalen-2-yl)propanamide 171 N-(1-(1-(L-alanyl)piperidin-4- 355.3 >100 yl)ethyl)isoquinoline-1-carboxamide 172 N-((1r,4r)-4-aminocyclohexyl)-1H-indazole- 259 >100 3-carboxamide 173 N-((1r,4r)-4-(3- 259.3 0.11 aminobutanamido)cyclohexyl)-2- oxoindoline-5-carboxamide 174 N-((1r,4r)-4-(2-aminoacetamido)cyclohexyl)- 331.2 0.63 2-oxoindoline-5-carboxamide 175 N-((1r,4r)-4-(2- 345.3 0.42 aminopropanamido)cyclohexyl)-2- oxoindoline-5-carboxamide 176 N-((1-(L-alanyl)-4-methylpiperidin-4- 359.1 3.52 yl)methyl)-2-oxoindoline-5-carboxamide 177 N-(((R)-1-(D-alanyl)pyrrolidin-3-yl)methyl)- 331.15 19.78 2-oxoindoline-5-carboxamide 178 N-(4-(3-amino-N- 359.3 3.4 methylpropanamido)cyclohexyl)-2- oxoindoline-5-carboxamide 179 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4-(5- 386.2 >100 methyl-1,2,4-oxadiazol-3-yl)benzamide 180 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3,5- 322.3 >100 dimethyl-1H-pyrazole-4-carboxamide 181 N-((1r,4r)-4-(3- 308.2 >100 aminopropanamido)cyclohexyl)-3,5- dimethyl-1H-pyrazole-4-carboxamide 182 N-((1r,4r)-4-aminocyclohexyl)-3,5-dimethyl- 237.1 >100 1H-pyrazole-4-carboxamide 183 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 320.2 >100 methylpyrimidine-5-carboxamide 184 N-((1r,4r)-4-(3- 306.3 35.78 aminopropanamido)cyclohexyl)-2- methylpyrimidine-5-carboxamide 185 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 320.3 >100 methylpyrazine-2-carboxamide 186 N-((1r,4r)-4-aminocyclohexyl)-5- 235.2 >100 methylpyrazine-2-carboxamide 187 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 320.3 >100 aminoisonicotinamide 188 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 321.2 >100 aminopyrazine-2-carboxamide 189 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-[1,1′- 380.3 >100 biphenyl]-4-carboxamide 190 N-((1r,4r)-4-aminocyclohexyl)-4- 298.2 >100 sulfamoylbenzamide 191 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 322.2 >100 hydroxypyridazine-3-carboxamide 192 N-((1r,4r)-4-aminocyclohexyl)-1H-indole-5- 258.2 >100 carboxamide 193 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 344.3 >100 benzo[d]imidazole-6-carboxamide 194 N-(1-(1-(L-alanyl)piperidin-4- 355.2 >100 yl)ethyl)isoquinoline-6-carboxamide 195 N-((1r,4r)-4-(2-(1H-indol-3- 343.2 >100 yl)acetamido)cyclohexyl)-3- aminopropanamide 196 N-((1r,4r)-4-(3- 341.2 >100 aminopropanamido)cyclohexyl)isoquinoline- 1-carboxamide 197 N-((1r,4r)-4-aminocyclohexyl)isoquinoline- 270.2 >100 1-carboxamide 198 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 361.2 41.66 fluoro-1H-indole-2-carboxamide 199 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 371.3 >100 hydroxyquinoline-4-carboxamide 200 N-((1r,4r)-4-(3- 357.2 23.31 aminopropanamido)cyclohexyl)-2- hydroxyquinoline-4-carboxamide 201 N-((1r,4r)-4-aminocyclohexyl)-2- 286.2 >100 hydroxyquinoline-4-carboxamide 202 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)- 358.3 59 5,6,7,8-tetrahydronaphthalene-2-carboxamide 203 N-((1r,4r)-4-(3- 344.2 11.21 aminopropanamido)cyclohexyl)-5,6,7,8- tetrahydronaphthalene-2-carboxamide 204 N-((1r,4r)-4-aminocyclohexyl)-5,6,7,8- 273.2 47.43 tetrahydronaphthalene-2-carboxamide 205 N-(1-(1-(L-alanyl)piperidin-4- 306.3 >100 yl)ethyl)pyrazine-2-carboxamide 206 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2-(4- 336.2 >100 fluorophenyl)acetamide 207 3-amino-N-((1r,4r)-4-(2-(4- 322.2 >100 fluorophenyl)acetamido)cyclohexyl)propanamide 208 N-((1r,4r)-4-aminocyclohexyl)-2-(4- 251.2 >100 fluorophenyl)acetamide 209 4-((1-(1-(L-alanyl)piperidin-4- 321.2 >100 yl)ethyl)carbamoyl)pyridine 1-oxide 210 4-(((1r,4r)-4- 236.2 >100 aminocyclohexyl)carbamoyl)pyridine 1- oxide 211 4-amino-N-((1r,4r)-4- 285.15 43.73 aminocyclohexyl)quinoline-6-carboxamide 212 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 370.3 15.16 aminoquinoline-6-carboxamide 213 (R)-2-oxo-N-(pyrrolidin-3- 260.15 17.95 ylmethyl)indoline-5-carboxamide 214 N-(4-(2-amino-N- 345.3 1.25 methylacetamido)cyclohexyl)-2-oxoindoline- 5-carboxamide 215 N-((1r,4r)-4-(3- 306.1 >100 aminopropanamido)cyclohexyl)-5- methylpyrazine-2-carboxamide 216 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2-(4- 428.2 >100 bromo-3,5-dimethyl-1H-pyrazol-1- yl)propanamide 217 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 385.3 >100 methyl-1-phenyl-1H-1,2,3-triazole-4- carboxamide 218 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4-(3- 400.3 76.96 methyl-5-oxo-4,5-dihydro-1H-pyrazol-1- yl)benzamide 219 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 358.2 >100 methyl-1H-indazole-6-carboxamide 220 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 384.2 >100 methoxy-2-naphthamide 221 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 385.1 >100 methoxyquinoline-4-carboxamide 222 N-((1r,4r)-4-(3- 371 >100 aminopropanamido)cyclohexyl)-2- methoxyquinoline-4-carboxamide 223 N-((1r,4r)-4-aminocyclohexyl)-2- 300 >100 methoxyquinoline-4-carboxamide 224 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 372.2 >100 oxo-4H-chromene-2-carboxamide 225 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 371.2 >100 hydroxyquinoline-2-carboxamide 226 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 371.2 >100 (4H-1,2,4-triazol-4-yl)benzamide 227 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 373.3 29.17 (pyrrolidin-1-yl)benzamide 228 N-(1-(1-(L-alanyl)piperidin-4- 361.2 >100 yl)ethyl)benzo[d]thiazole-6-carboxamide 229 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 377.2 77.9 chloro-1H-indole-2-carboxamide 230 N-((1r,4r)-4-(3- 363.1 37.47 aminopropanamido)cyclohexyl)-5-chloro- 1H-indole-2-carboxamide 231 N-((1r,4r)-4-aminocyclohexyl)-5-chloro-1H- 292.1 91.53 indole-2-carboxamide 232 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 343.3 >100 indole-2-carboxamide 233 N-((1r,4r)-4-(3- 329.3 >100 aminopropanamido)cyclohexyl)-1H-indole- 2-carboxamide 234 N-((1r,4r)-4-aminocyclohexyl)-1H-indole-2- 258.2 >100 carboxamide 235 N-((1r,4r)-4-(3- 329.2 13.44 aminopropanamido)cyclohexyl)-1H-indole- 5-carboxamide 236 5-((1-(1-(L-alanyl)piperidin-4- 362.2 >100 yl)ethyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-oxide 237 N-(1-(1-(L-alanyl)piperidin-4- 346.2 >100 yl)ethyl)benzo[c][1,2,5]oxadiazole-5- carboxamide 238 N-(1-(1-(L-alanyl)piperidin-4- 356.3 >100 yl)ethyl)quinoxaline-2-carboxamide 239 N-(1-(1-(L-alanyl)piperidin-4- 350.2 >100 yl)ethyl)imidazo[2,1-b]thiazole-6- carboxamide 241 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 336.3 82.88 (1H-imidazol-1-yl)butanamide 242 N-((1r,4r)-4-aminocyclohexyl)-5-fluoro-1H- 276 >100 indole-2-carboxamide 243 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 344.2 72.93 benzo[d]imidazole-2-carboxamide 244 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 357.2 >100 methyl-1H-indole-2-carboxamide 245 N-((1r,4r)-4-(3- 343.3 >100 aminopropanamido)cyclohexyl)-1-methyl- 1H-indole-2-carboxamide 246 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 272.2 >100 indole-2-carboxamide 247 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 320.2 >100 aminonicotinamide 248 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 343.3 >100 indole-4-carboxamide 249 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 321.2 65.86 hydroxyisonicotinamide 250 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 321.2 >100 hydroxyisonicotinamide 251 N-((1r,4r)-4-aminocyclohexyl)picolinamide 220.1 >100 252 N-((1r,4r)-4-(3- 292.1 37.36 aminopropanamido)cyclohexyl)pyrazine-2- carboxamide 253 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 308.2 64.91 methyl-1H-imidazole-2-carboxamide 254 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 319.3 >100 methylisonicotinamide 255 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 319.3 73.38 methylnicotinamide 256 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 319.3 61.59 methylnicotinamide 257 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 319.3 >100 methylnicotinamide 258 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 325.3 >100 methylisothiazole-4-carboxamide 259 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 308.3 >100 methyl-1H-pyrazole-3-carboxamide 260 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 364.3 >100 (tert-butyl)-1-methyl-1H-pyrazole-5- carboxamide 261 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 336.2 >100 methoxypyrazine-2-carboxamide 262 (1r,4S)-N-(1-(1-(L-alanyl)piperidin-4- 325.2 >100 yl)ethyl)-4-aminocyclohexane-1- carboxamide 263 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 406.2 >100 chloro-2-(trifluoromethyl)benzamide 264 4-(((1r,4r)-4-(3- 307.2 >100 aminopropanamido)cyclohexyl)carbamoyl)pyridine 1-oxide 265 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 323.2 >100 fluoropicolinamide 266 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2,2- 384.3 >100 difluorobenzo[d][1,3]dioxole-4-carboxamide 267 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 323.2 >100 fluoroisonicotinamide 268 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 343.3 >100 indole-3-carboxamide 269 N-((1r,4r)-4-aminocyclohexyl)pyrimidine-2- 221.1 >100 carboxamide 270 N-((1r,4r)-4-(3- 308.2 >100 aminopropanamido)cyclohexyl)-6- hydroxypyridazine-3-carboxamide 271 N-((1r,4r)-4-aminocyclohexyl)-6- 237.2 >100 hydroxypyridazine-3-carboxamide 272 N-((1r,4r)-4-(3- 329.2 37.25 aminopropanamido)cyclohexyl)-1H-indole- 6-carboxamide 273 N-((1r,4r)-4-aminocyclohexyl)-5-methyl-1- 300.1 >100 phenyl-1H-1,2,3-triazole-4-carboxamide 274 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4,6- 349.3 >100 dimethyl-2-oxo-1,2-dihydropyridine-3- carboxamide 275 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 273 >100 indazole-6-carboxamide 276 N-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2- 299.1 >100 naphthamide 277 N-((1r,4r)-4-aminocyclohexyl)-4-oxo-4H- 287 >100 chromene-2-carboxamide 278 N-((1r,4r)-4-aminocyclohexyl)-4-(4H-1,2,4- 286 >100 triazol-4-yl)benzamide 279 N-((1r,4r)-4-(3- 359.1 43.65 aminopropanamido)cyclohexyl)-4- (pyrrolidin-1-yl)benzamide 280 N-((1r,4r)-4-aminocyclohexyl)-4-(pyrrolidin- 288.1 48.03 1-yl)benzamide 281 N-((1r,4r)-4-(3- 347 28.96 aminopropanamido)cyclohexyl)benzo[d]thiazole- 6-carboxamide 283 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 343.2 >100 indole-5-carboxamide 284 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2,2- 384.2 >100 difluorobenzo[d][1,3]dioxole-5-carboxamide 285 N-((1r,4r)-4-aminocyclohexyl)-2,2- 299.2 69.12 difluorobenzo[d][1,3]dioxole-5-carboxamide 286 5-(((1r,4r)-4- 277.1 >100 aminocyclohexyl)carbamoyl)benzo[c][1,2,5] oxadiazole 1-oxide 287 N-((1r,4r)-4- 261 >100 aminocyclohexyl)benzo[c][1,2,5]oxadiazole- 5-carboxamide 288 4-amino-N-((1r,4r)-4-(3- 306.1 >100 aminopropanamido)cyclohexyl)nicotinamide 289 4-amino-N-((1r,4r)-4- 235.2 >100 aminocyclohexyl)nicotinamide 290 N-((1r,4r)-4-(3- 329.2 >100 aminopropanamido)cyclohexyl)-1H-indole- 4-carboxamide 291 N-((1r,4r)-4-aminocyclohexyl)-1H-indole-4- 258.2 >100 carboxamide 292 N-((1r,4r)-4-aminocyclohexyl)-2- 236.2 >100 hydroxyisonicotinamide 293 N-((1r,4r)-4-aminocyclohexyl)-2- 236.1 >100 hydroxyisonicotinamide 294 N-((1r,4r)-4-(3- 307.2 >100 aminopropanamido)cyclohexyl)-6- hydroxynicotinamide 295 N-((1r,4r)-4-aminocyclohexyl)-6- 236.2 >100 hydroxynicotinamide 296 N-(1-(1-(L-alanyl)piperidin-4- 305.2 >100 yl)ethyl)picolinamide 297 N-(4-(3- 291.2 44.24 aminopropanamido)cyclohexyl)picolinamide 298 N-((1r,4r)-4-aminocyclohexyl)pyrazine-2- 221.2 >100 carboxamide 299 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 454.3 >100 (tert-butyl)-1-(3-methylbenzyl)-1H-pyrazole- 5-carboxamide 300 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-7- 357.2 >100 methyl-1H-indole-2-carboxamide 301 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 335.2 >100 methoxypicolinamide 302 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 336.2 >100 methoxypyrazine-2-carboxamide 303 (1r,4r)-4-amino-N-((1r,4r)-4-(3- 311.2 >100 aminopropanamido)cyclohexyl)cyclohexane- 1-carboxamide 304 (1r,4r)-4-amino-N-((1r,4r)-4- 240.1 >100 aminocyclohexyl)cyclohexane-1- carboxamide 305 (2S,4S)-N-(1-(1-(L-alanyl)piperidin-4- 315.2 55.92 yl)ethyl)-4-fluoropyrrolidine-2-carboxamide 306 (3R)-N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)- 359.3 48.06 1,2,3,4-tetrahydroisoquinoline-3- carboxamide 307 N-((1r,4r)-4-aminocyclohexyl)-2,2- 299 >100 difluorobenzo[d][1,3]dioxole-4-carboxamide 308 N-((1r,4r)-4-aminocyclohexyl)-3- 238.2 >100 fluoroisonicotinamide 309 N-(1-(1-(L-alanyl)piperidin-4- 311.2 >100 yl)ethyl)thiazole-5-carboxamide 310 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 321.2 >100 hydroxypicolinamide 311 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 324.2 >100 oxo-1,4,5,6-tetrahydropyridazine-3- carboxamide 312 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 344.2 >100 indazole-3-carboxamide 313 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 354.2 70.71 (3,5-difluorophenyl)acetamide 314 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 319.2 >100 (pyridin-3-yl)acetamide 315 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 320.3 >100 (pyrimidin-5-yl)acetamide 316 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 308.2 >100 (1H-imidazol-1-yl)acetamide 317 N-((1r,4r)-4-(3- 336 >100 aminopropanamido)cyclohexyl)imidazo[2,1- b]thiazole-6-carboxamide 318 N-((1r,4r)-4-aminocyclohexyl)imidazo[2,1- 265 >100 b]thiazole-6-carboxamide 319 N-((1r,4r)-4-aminocyclohexyl)imidazo[2,1- 265.2 >100 b]thiazole-6-carboxamide 320 N-((1r,4r)-4-aminocyclohexyl)-2- 235.1 >100 methylpyrimidine-5-carboxamide 321 2-amino-N-((1r,4r)-4-(3- 306.2 16.59 aminopropanamido)cyclohexyl)isonicotinamide 322 2-amino-N-((1r,4r)-4- 235.1 >100 aminocyclohexyl)isonicotinamide 323 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 383 >100 sulfamoylbenzamide 324 N-((1r,4r)-4-aminocyclohexyl)-4,6-dimethyl- 264.1 >100 2-oxo-1,2-dihydropyridine-3-carboxamide 325 N-((1r,4r)-4-(3- 344.3 >100 aminopropanamido)cyclohexyl)-1-methyl- 1H-indazole-6-carboxamide 326 N-((1r,4r)-4-(3- 370.3 28 aminopropanamido)cyclohexyl)-6-methoxy- 2-naphthamide 327 N-((1r,4r)-4-(3- 358.2 >100 aminopropanamido)cyclohexyl)-4-oxo-4H- chromene-2-carboxamide 328 N-((1r,4r)-4-aminocyclohexyl)-4- 286.2 >100 hydroxyquinoline-2-carboxamide 329 N-((1r,4r)-4-(3- 357.3 >100 aminopropanamido)cyclohexyl)-4-(4H-1,2,4- triazol-4-yl)benzamide 330 N-((1r,4r)-4-(3- 370.2 7.49 aminopropanamido)cyclohexyl)-2,2- difluorobenzo[d][1,3]dioxole-5-carboxamide 331 5-(((1r,4r)-4-(3- 348.2 85.12 aminopropanamido)cyclohexyl)carba- moyl)benzo[c][1,2,5]oxadiazole 1-oxide 332 N-((1r,4r)-4-(3- 332.2 >100 aminopropanamido)cyclohexyl)benzo[c][1,2,5]oxa- diazole-5-carboxamide 333 N-((1r,4r)-4-aminocyclohexyl)-4-(1H- 251.1 >100 imidazol-1-yl)butanamide 334 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2-(6- 412.3 34.86 methoxynaphthalen-2-yl)propanamide 335 N-((1r,4r)-4-(3- 347.2 >100 aminopropanamido)cyclohexyl)-5-fluoro-1H- indole-2-carboxamide 336 N-((1r,4r)-4-aminocyclohexyl)-1H- 259.1 >100 benzo[d]imidazole-2-carboxamide 337 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 223.1 >100 imidazole-2-carboxamide 338 (1r,4r)-N-(1-(1-(L-alanyl)piperidin-4- 320.3 >100 yl)ethyl)bicyclo[2.2.1]hept-5-ene-2- carboxamide 339 N-((1r,4r)-4-aminocyclohexyl)-4- 234.1 >100 methylnicotinamide 340 N-((1r,4r)-4-(3- 440.3 >100 aminopropanamido)cyclohexyl)-3-(tert- butyl)-1-(3-methylbenzyl)-1H-pyrazole-5- carboxamide 341 N-((1r,4r)-4-aminocyclohexyl)-3-(tert-butyl)- 369.1 >100 1-(3-methylbenzyl)-1H-pyrazole-5- carboxamide 342 N-((1r,4r)-4-(3- 343.2 37.68 aminopropanamido)cyclohexyl)-7-methyl- 1H-indole-2-carboxamide 343 N-((1r,4r)-4-aminocyclohexyl)-7-methyl-1H- 272.2 68.49 indole-2-carboxamide 344 N-((1r,4r)-4-(3- 305.1 36.4 aminopropanamido)cyclohexyl)-5- methylnicotinamide 345 N-((1r,4r)-4-aminocyclohexyl)-5- 234.2 50.67 methylnicotinamide 346 N-((1r,4r)-4-aminocyclohexyl)-6- 234.1 >100 methylnicotinamide 347 N-((1r,4r)-4-(3- 311.2 >100 aminopropanamido)cyclohexyl)-3- methylisothiazole-4-carboxamide 348 N-((1r,4r)-4-aminocyclohexyl)-3- 240.2 >100 methylisothiazole-4-carboxamide 349 N-((1r,4r)-4-(3- 294.2 >100 aminopropanamido)cyclohexyl)-1-methyl- 1H-pyrazole-3-carboxamide 350 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 223.2 >100 pyrazole-3-carboxamide 351 N-((1r,4r)-4-(3- 350.3 >100 aminopropanamido)cyclohexyl)-3-(tert- butyl)-1-methyl-1H-pyrazole-5-carboxamide 352 N-((1r,4r)-4-aminocyclohexyl)-3-(tert-butyl)- 279.3 >100 1-methyl-1H-pyrazole-5-carboxamide 353 N-((1r,4r)-4-(3- 321.2 >100 aminopropanamido)cyclohexyl)-6- methoxypicolinamide 354 N-((1r,4r)-4-aminocyclohexyl)-6- 250.2 >100 methoxypicolinamide 355 N-((1r,4r)-4-(3- 322 >100 aminopropanamido)cyclohexyl)-6- methoxypyrazine-2-carboxamide 356 N-((1r,4r)-4-aminocyclohexyl)-6- 251.2 >100 methoxypyrazine-2-carboxamide 357 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 320.2 >100 aminopicolinamide 358 N-((1r,4r)-4-aminocyclohexyl)-4-chloro-2- 320.9 >100 (trifluoromethyl)benzamide 359 N-((1r,4r)-4-aminocyclohexyl)thiazole-5- 226.1 >100 carboxamide 360 N-((1r,4r)-4-aminocyclohexyl)-1H-indole-3- 258.1 >100 carboxamide 361 N-((1r,4r)-4-(3- 307.1 >100 aminopropanamido)cyclohexyl)-5- hydroxypicolinamide 362 N-((1r,4r)-4-aminocyclohexyl)-2-(3,5- 269.2 >100 difluorophenyl)acetamide 363 3-amino-N-((1r,4r)-4-(2-(pyridin-3- 305.1 >100 yl)acetamido)cyclohexyl)propanamide 364 3-amino-N-((1r,4r)-4-(2-(pyrimidin-5- 306.2 >100 yl)acetamido)cyclohexyl)propanamide 365 N-((1r,4r)-4-aminocyclohexyl)-2-(pyrimidin- 235.2 >100 5-yl)acetamide 366 N-((1r,4r)-4-(2-(1H-imidazol-1- 294.1 >100 yl)acetamido)cyclohexyl)-3- aminopropanamide 367 N-((1r,4r)-4- 276.1 >100 aminocyclohexyl)benzo[d]thiazole-2- carboxamide 368 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 343.3 12.33 indole-6-carboxamide 369 N-((1r,4r)-4-(3- 330.1 65.22 aminopropanamido)cyclohexyl)-1H- benzo[d]imidazole-5-carboxamide 370 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 373.2 >100 methoxy-1H-indole-3-carboxamide 371 N-((1r,4r)-4-(3- 359.2 >100 aminopropanamido)cyclohexyl)-4-methoxy- 1H-indole-3-carboxamide 372 N-((1r,4r)-4-aminocyclohexyl)-4-methoxy- 288.1 >100 1H-indole-3-carboxamide 373 N-((1r,4r)-4-(3- 342.1 >100 aminopropanamido)cyclohexyl)quinoxaline- 2-carboxamide 374 N-((1r,4r)-4-(3- 330.3 86.56 aminopropanamido)cyclohexyl)-1H- benzo[d]imidazole-2-carboxamide 375 N-((1r,4r)-4-(3- 322.2 >100 aminopropanamido)cyclohexyl)-4-(1H- imidazol-1-yl)butanamide 376 N-((1r,4r)-4-(3- 307.2 >100 aminopropanamido)cyclohexyl)-2- hydroxyisonicotinamide 378 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 321.1 >100 hydroxynicotinamide 379 N-((1r,4r)-4-(3- 305.1 >100 aminopropanamido)cyclohexyl)-3- methylisonicotinamide 380 N-((1r,4r)-4-aminocyclohexyl)-3- 234.1 >100 methylisonicotinamide 381 N-((1r,4r)-4-(3- 305.1 >100 aminopropanamido)cyclohexyl)-4- methylnicotinamide 382 N-((1r,4r)-4-(3- 305.2 >100 aminopropanamido)cyclohexyl)-6- methylnicotinamide 383 N-((1r,4r)-4-(3- 322.1 >100 aminopropanamido)cyclohexyl)-5- methoxypyrazine-2-carboxamide 384 N-((1r,4r)-4-aminocyclohexyl)-5- 251 >100 methoxypyrazine-2-carboxamide 385 6-amino-N-((1r,4r)-4-(3- 306.2 >100 aminopropanamido)cyclohexyl)picolinamide 386 6-amino-N-((1r,4r)-4- 235.1 >100 aminocyclohexyl)picolinamide 387 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 320.2 >100 aminonicotinamide 388 6-amino-N-((1r,4r)-4-(3- 306.2 >100 aminopropanamido)cyclohexyl)nicotinamide 389 N-((1r,4r)-4-aminocyclohexyl)-6- 238.2 >100 fluoropicolinamide 390 N-((1r,4r)-4-(3- 309.2 >100 aminopropanamido)cyclohexyl)-3- fluoroisonicotinamide 391 N-((1r,4r)-4-(3- 329.1 >100 aminopropanamido)cyclohexyl)-1H-indole- 3-carboxamide 392 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 319.2 >100 methylisonicotinamide 393 N-((1r,4r)-4-(3- 305.2 >100 aminopropanamido)cyclohexyl)-2- methylisonicotinamide 394 N-((1r,4r)-4-aminocyclohexyl)-2- 234.1 >100 methylisonicotinamide 395 N-(1-(1-(L-alanyl)piperidin-4- 361.2 >100 yl)ethyl)benzo[d]thiazole-2-carboxamide 396 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 325 10.61 methylthiazole-2-carboxamide 397 N-((1r,4r)-4-(3- 311 27.42 aminopropanamido)cyclohexyl)-5- methylthiazole-2-carboxamide 398 N-((1r,4r)-4-aminocyclohexyl)-5- 240.1 >100 methylthiazole-2-carboxamide 399 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 359.2 >100 oxoindoline-4-carboxamide 400 N-((1r,4r)-4-aminocyclohexyl)-2- 274.2 >100 oxoindoline-4-carboxamide 401 N-((1r,4r)-4-(3- 371.1 >100 aminopropanamido)cyclohexyl)-5-methyl-1- phenyl-1H-1,2,3-triazole-4-carboxamide 402 N-((1r,4r)-4-(3- 335.2 >100 aminopropanamido)cyclohexyl)-4,6- dimethyl-2-oxo-1,2-dihydropyridine-3- carboxamide 403 N-((1r,4r)-4-aminocyclohexyl)-4-(3-methyl- 315.1 >100 5-oxo-4,5-dihydro-1H-pyrazol-1- yl)benzamide 404 N-((1r,4r)-4-(3- 357.2 >100 aminopropanamido)cyclohexyl)-4- hydroxyquinoline-2-carboxamide 405 N-((1r,4r)-4-aminocyclohexyl)quinoxaline-2- 271.2 >100 carboxamide 406 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 358.2 >100 (1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide 407 N-((1r,4r)-4-(2-(1H-pyrrolo[3,2-b]pyridin-3- 344.2 >100 yl)acetamido)cyclohexyl)-3- aminopropanamide 408 N-((1r,4r)-4-aminocyclohexyl)-2-(1H- 273.2 >100 pyrrolo[3,2-b]pyridin-3-yl)acetamide 409 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 321.2 70.41 hydroxynicotinamide 410 N-((1r,4r)-4-(3- 307.3 44.48 aminopropanamido)cyclohexyl)-2- hydroxynicotinamide 411 N-((1r,4r)-4-aminocyclohexyl)-2- 236.2 >100 hydroxynicotinamide 412 N-((1r,4r)-4-(3- 294.1 >100 aminopropanamido)cyclohexyl)-1-methyl- 1H-imidazole-2-carboxamide 413 N-(l-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 308.1 >100 methyl-1H-pyrazole-5-carboxamide 414 N-((1r,4r)-4-(3- 294.1 >100 aminopropanamido)cyclohexyl)-1-methyl- 1H-pyrazole-5-carboxamide 415 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 223.1 >100 pyrazole-5-carboxamide 416 (1R,4R)-N-((1r,4R)-4-(3- 306.1 >100 aminopropanamido)cyclohexyl)bicyclo[2.2.1]hept- 5-ene-2-carboxamide 417 (1r,4r)-N-((1r,4R)-4- 235.1 >100 aminocyclohexyl)bicyclo[2.2.1]hept-5-ene-2- carboxamide 418 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 320.3 >100 aminopicolinamide 419 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 321.2 >100 aminopyrimidine-5-carboxamide 420 4-amino-N-((1r,4r)-4-(3- 307.2 >100 aminopropanamido)cyclohexyl)pyrimidine- 5-carboxamide 421 4-amino-N-((1r,4r)-4- 236.1 >100 aminocyclohexyl)pyrimidine-5-carboxamide 422 N-((1r,4r)-4-(3- 309.2 >100 aminopropanamido)cyclohexyl)-6- fluoropicolinamide 423 N-((1r,4r)-4-aminocyclohexyl)-5- 236.2 >100 hydroxypicolinamide 424 N-((1r,4r)-4-aminocyclohexyl)-6-oxo- 239.1 >100 1,4,5,6-tetrahydropyridazine-3-carboxamide 425 N-((1r,4r)-4-(3- 330.1 37.49 aminopropanamido)cyclohexyl)-1H- indazole-3-carboxamide 426 N-((1r,4r)-4-aminocyclohexyl)-2-(1H- 223.1 >100 imidazol-1-yl)acetamide 427 N-((1r,4r)-4-(3- 347.2 >100 aminopropanamido)cyclohexyl)benzo[d]thiazole- 2-carboxamide 428 (1r,4r)-4-amino-N-(2-oxoindolin-5- 274.1 30.6 yl)cyclohexane-1-carboxamide 429 N-((1r,4r)-4-aminocyclohexyl)-2- 310 14.5 oxoindoline-5-sulfonamide 430 N-((1r,4r)-4-(3- 345.2 >100 aminopropanamido)cyclohexyl)-2- oxoindoline-4-carboxamide 431 3-amino-N-((1r,4r)-4-(2-(4-bromo-3,5- >100 dimethyl-1H-pyrazol-1- yl)propanamido)cyclohexyl)propanamide 432 N-((1r,4r)-4-(3- 386.3 36.97 aminopropanamido)cyclohexyl)-4-(3-methyl- 5-oxo-4,5-dihydro-1H-pyrazol-1- yl)benzamide 433 (2R,4S)-N-(1-(1-(L-alanyl)piperidin-4- 313.2 45.65 yl)ethyl)-4-hydroxypyrrolidine-2- carboxamide 434 (2R,4S)-N-((1r,4r)-4-(3- 299.2 >100 aminopropanamido)cyclohexyl)-4- hydroxypyrrolidine-2-carboxamide 435 (2R,4S)-N-((1r,4r)-4-aminocyclohexyl)-4- 228.1 >100 hydroxypyrrolidine-2-carboxamide 436 (R)-N-((1r,4r)-4-aminocyclohexyl)-1,2,3,4- 274.1 12.51 tetrahydroquinoline-2-carboxamide 437 5-amino-N-((1r,4r)-4-(3- 306.2 >100 aminopropanamido)cyclohexyl)picolinamide 438 5-amino-N-((1r,4r)-4- 235.2 >100 aminocyclohexyl)picolinamide 439 N-((1r,4r)-4-(3- 392.2 >100 aminopropanamido)cyclohexyl)-4-chloro-2- (trifluoromethyl)benzamide 440 N-((1r,4r)-4-(3- 370.2 >100 aminopropanamido)cyclohexyl)-2,2- difluorobenzo[d][1,3]dioxole-4-carboxamide 441 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3,5- 386.1 37.45 dihydroxy-2-naphthamide 442 N-((1r,4r)-4-(3- 297.2 >100 aminopropanamido)cyclohexyl)thiazole-5- carboxamide 443 3-amino-N-((1r,4r)-4-(2-(3,5- 340.2 >100 difluorophenyl)acetamido)cyclohexyl)propan amide 444 5-acetamido-N-((1r,4r)-4- 277 >100 aminocyclohexyl)picolinamide 445 N-(1-(1-(L-alanyl)piperidin-4- 345 >100 yl)ethyl)imidazo[1,2-b]pyridazine-2- carboxamide 446 N-((1r,4r)-4-(3- 331.1 >100 aminopropanamido)cyclohexyl)imidazo[1,2- b]pyridazine-2-carboxamide 447 N-((1r,4r)-4-aminocyclohexyl)imidazo[1,2- 260 >100 b]pyridazine-2-carboxamide 448 N-((1r,4r)-4-aminocyclohexyl)-2-(2- 288.2 >100 oxoindolin-5-yl)acetamide 449 3-amino-N-((1r,4r)-4-((2-oxoindoline)-5- 381.1 >100 sulfonamido)cyclohexyl)propanamide 450 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 389.2 25.37 methyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 451 N-((1r,4r)-4-(3- 375.2 9.9 aminopropanamido)cyclohexyl)-2-methyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 452 N-((1r,4r)-4-aminocyclohexyl)-2-methyl-3- 304.2 39.15 oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 453 N-((1r,4r)-4-((R)-3- 359.2 0.26 >40 aminobutanamido)cyclohexyl)-2- oxoindoline-5-carboxamide 454 N-((1r,4r)-4-aminocyclohexyl)-2-(4-bromo- 342.9 >100 3,5-dimethyl-1H-pyrazol-1-yl)propanamide 455 N-((1r,4r)-4-aminocyclohexyl)-4-(1H-1,2,4- 286.2 >100 triazol-1-yl)benzamide 456 N-((1r,4r)-4-(3- 357.2 21.97 aminopropanamido)cyclohexyl)-2- hydroxyquinoline-3-carboxamide 457 N-((1r,4r)-4-aminocyclohexyl)-2-(3- 301 >100 (trifluoromethyl)phenyl)acetamide 458 3-amino-N-((1r,4r)-4-aminocyclohexyl)-2- 299.1 >100 methylquinoline-4-carboxamide 459 (3R)-N-(4-aminocyclohexyl)-1,2,3,4- 274.1 >100 tetrahydroisoquinoline-3-carboxamide 460 N-((1r,4r)-4-aminocyclohexyl)-3,5- 301 20.71 dihydroxy-2-naphthamide 461 5-(2-(piperidin-4-yl)acetyl)octahydro-2H- 266.1 >100 pyrrolo[3,2-c]pyridin-2-one 462 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 362.1 >100 acetamidopicolinamide 463 5-acetamido-N-((1r,4r)-4-(3- 348 >100 aminopropanamido)cyclohexyl)picolinamide 464 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 336.2 32.68 cyclopropyl-1,2,4-oxadiazole-3-carboxamide 465 3-amino-N-((1r,4r)-4-(2-(2-oxoindolin-5- 359.2 38.81 yl)acetamido)cyclohexyl)propanamide 466 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2-(2- 373.2 60 oxoindolin-5-yl)acetamide 467 (1r,4r)-4-(3-aminopropanamido)-N-(2- 345 4.46 oxoindolin-5-yl)cyclohexane-1-carboxamide 468 3-amino-N-(2,2-dimethyl-3-((2-oxoindoline)- 369.2 18.32 5-sulfonamido)propyl)propanamide 469 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1- 359.2 >100 oxoisoindoline-5-carboxamide 470 N-((1r,4r)-4-aminocyclohexyl)-2,3- 288 7.46 dioxoindoline-5-carboxamide 471 N-((1r,4r)-4-(3- 345.2 0.61 aminopropanamido)cyclohexyl)-2- oxoindoline-5-carboxamide 472 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 371.3 >100 (1H-1,2,4-triazol-1-yl)benzamide 473 N-((1r,4r)-4-(3- 357.2 53.11 aminopropanamido)cyclohexyl)-4-(1H-1,2,4- triazol-1-yl)benzamide 474 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 371.2 22.09 hydroxyquinoline-3-carboxamide 475 N-((1r,4r)-4-aminocyclohexyl)-2- 286.2 22.16 hydroxyquinoline-3-carboxamide 476 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2-(3- 386.1 51.13 (trifluoromethyl)phenyl)acetamide 477 3-amino-N-((1r,4r)-4-(2-(3- 372 22.78 (trifluoromethyl)phenyl)acetamido)cyclo- hexyl)propanamide 478 3-amino-N-((1r,4r)-4-(3- 370.2 31.62 aminopropanamido)cyclohexyl)-2- methylquinoline-4-carboxamide 479 N-((1r,4r)-4-(3- 372 5.02 aminopropanamido)cyclohexyl)-3,5- dihydroxy-2-naphthamide 480 N-((1r,4r)-4-aminocyclohexyl)-3- 236.2 >100 hydroxypicolinamide 481 N-((1r,4r)-4-(3- 310.2 15.1 aminopropanamido)cyclohexyl)-6-oxo- 1,4,5,6-tetrahydropyridazine-3-carboxamide 482 (E)-N-((1r,4r)-4-(3- 306.1 71.06 aminopropanamido)cyclohexyl)-3-(1H- imidazol-4-yl)acrylamide 483 5-(2-(1-(3-aminopropanoyl)piperidin-4- 337.2 10.25 yl)acetyl)octahydro-2H-pyrrolo[3,2- c]pyridin-2-one 484 N-((1r,4r)-4-aminocyclohexyl)-5- 251.1 85.66 cyclopropyl-1,2,4-oxadiazole-3-carboxamide 485 N-((1r,4r)-4-(3- 322.1 12.92 aminopropanamido)cyclohexyl)-5- cyclopropyl-1,2,4-oxadiazole-3-carboxamide 486 2-amino-N-(2,2-dimethyl-3-((2-oxoindoline)- 355 18.82 5-sulfonamido)propyl)acetamide 487 N-((1r,4r)-4-aminocyclohexyl)-1- 274.1 37.89 oxoisoindoline-5-carboxamide 488 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2,3- 373.1 14.08 dioxoindoline-5-carboxamide 489 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 384.3 31.62 amino-2-methylquinoline-4-carboxamide 490 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 393.2 0.43 >40 chloro-2-oxoindoline-5-carboxamide 491 N-((1r,4r)-4-(3- 379.2 0.15 >40 aminopropanamido)cyclohexyl)-6-chloro-2- oxoindoline-5-carboxamide 492 N-((1r,4r)-4-aminocyclohexyl)-6-chloro-2- 308.1 1.59 oxoindoline-5-carboxamide 493 N-((1r,4r)-4-aminocyclohexyl)-4- 237.1 >50 hydroxypyrimidine-5-carboxamide 494 (E)-N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)- 320.2 >100 3-(1H-imidazol-4-yl)acrylamide 495 (E)-N-((1r,4r)-4-aminocyclohexyl)-3-(1H- 235.1 >100 imidazol-4-yl)acrylamide 496 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1H- 345.2 6.57 pyrazolo[3,4-c]pyridine-5-carboxamide 497 N-((1r,4r)-4-aminocyclohexyl)-1H- 260 35.73 pyrazolo[3,4-c]pyridine-5-carboxamide 498 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-6- 379 51 fluorobenzo[d]thiazole-2-carboxamide 499 N-((1r,4r)-4-(3- 365.2 86.27 aminopropanamido)cyclohexyl)-6- fluorobenzo[d]thiazole-2-carboxamide 500 N-((1r,4r)-4-aminocyclohexyl)-6- 294.1 >100 fluorobenzo[d]thiazole-2-carboxamide 501 1-(2-amino-2-oxoethyl)-N-((1r,4r)-4- 267.2 50 aminocyclohexyl)-1H-1,2,3-triazole-4- carboxamide 502 N-((1r,4r)-4-aminocyclohexyl)-1H- 209.1 >100 imidazole-2-carboxamide 503 N-((1r,4r)-4-(3- 345.2 >100 aminopropanamido)cyclohexyl)-1- oxoisoindoline-5-carboxamide 504 N-((1r,4r)-4-(3- 359 5.38 aminopropanamido)cyclohexyl)-2,3- dioxoindoline-5-carboxamide 505 N-((1r,4r)-4-(3- 345.2 16.1 aminopropanamido)cyclohexyl)-2- oxoindoline-7-carboxamide 506 N-(4-aminocyclohexyl)-2-oxoindoline-7- 274.2 42.25 carboxamide 507 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 224.2 >100 1,2,4-triazole-5-carboxamide 508 3-amino-N-((1r,4r)-4-aminocyclohexyl)-1H- 225 >50 1,2,4-triazole-5-carboxamide 509 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4- 322.1 >50 hydroxypyrimidine-5-carboxamide 510 N-((1r,4r)-4-(3- 308.1 >50 aminopropanamido)cyclohexyl)-4- hydroxypyrimidine-5-carboxamide 511 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 321.1 >50 hydroxypicolinamide 512 N-((1r,4r)-4-(3- 307 >50 aminopropanamido)cyclohexyl)-3- hydroxypicolinamide 513 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 321.2 >50 hydroxynicotinamide 514 N-((1r,4r)-4-(3- 307.1 >50 aminopropanamido)cyclohexyl)-5- hydroxynicotinamide 515 N-((1r,4r)-4-aminocyclohexyl)-5- 236.1 >50 hydroxynicotinamide 516 1-(2-amino-2-oxoethyl)-N-((1r,4r)-4-(3- 338.2 >50 aminopropanamido)cyclohexyl)-1H-1,2,3- triazole-4-carboxamide 517 N-(4-aminocyclohexyl)-1H-imidazole-4- 209.2 >50 carboxamide 518 N-(4-(3-aminopropanamido)cyclohexyl)-1H- 280.2 >50 imidazole-2-carboxamide 519 N-((1r,4r)-4-(3- 343.2 >50 aminopropanamido)cyclohexyl)-2-methyl- 1H-indole-5-carboxamide 520 N-((1r,4r)-4-aminocyclohexyl)-2-methyl-1H- 272.2 >50 indole-5-carboxamide 521 N-((1r,4r)-4-aminocyclohexyl)-1H- 209.2 >50 imidazole-4-carboxamide 522 N-((1r,4r)-4-aminocyclohexyl)-2-methyl-1H- 223.2 >50 imidazole-5-carboxamide 523 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-4H- 295.1 >50 1,2,4-triazole-3-carboxamide 525 N-((1r,4r)-4-(3- 281.1 >50 aminopropanamido)cyclohexyl)-4H-1,2,4- triazole-3-carboxamide 527 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 328 >50 chloro-1H-pyrazole-3-carboxamide 528 N-((1r,4r)-4-(3- 314 >50 aminopropanamido)cyclohexyl)-5-chloro- 1H-pyrazole-3-carboxamide 529 N-((1r,4r)-4-(3- 331.2 4.45 aminopropanamido)cyclohexyl)-1H- pyrazolo[3, 4-c]pyridine-5-carboxamide 530 N-((1r,4r)-4-(3- 297.1 >50 aminopropanamido)cyclohexyl)-5-oxo-4,5- dihydro-1H-1,2,4-triazole-3-carboxamide 531 N-((1r,4r)-4-aminocyclohexyl)-5-oxo-4,5- 226.1 >50 dihydro-1H-1,2,4-triazole-3-carboxamide 532 N-((1r,4r)-4-(3- 348.1 >50 aminopropanamido)cyclohexyl)thiazolo[5,4- c]pyridine-2-carboxamide 533 N-((1r,4r)-4-aminocyclohexyl)thiazolo[5,4- 277.1 >50 c]pyridine-2-carboxamide 534 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-1-(2- 352.2 >50 amino-2-oxoethyl)-1H-1,2,3-triazole-4- carboxamide 535 N-((1r,4r)-4-aminocyclohexyl)-5-ethyl-1H- 238.1 >50 1,2,4-triazole-3-carboxamide 536 N-((1r,4r)-4-(3- 309.2 >50 aminopropanamido)cyclohexyl)-5-ethyl-4H- 1,2,4-triazole-3-carboxamide 537 N-((1r,4r)-4-(3- 280.2 >50 aminopropanamido)cyclohexyl)-1H- imidazole-4-carboxamide 538 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-2- 357.2 >50 methyl-1H-indole-5-carboxamide 539 N-((1R,4r)-4-((1r,4R)-4-aminocyclohexane- 335.2 >50 1-carboxamido)cyclohexyl)-1H-1,2,4- triazole-5-carboxamide 540 N-((1r,4r)-4-(4- 295.1 >50 aminobutanamido)cyclohexyl)-4H-1,2,4- triazole-3-carboxamide 541 N-((1r,4r)-4-aminocyclohexyl)-5-chloro-1H- 244.1 >50 1,2,4-triazole-3-carboxamide 542 N-((1r,4r)-4-aminocyclohexyl)-5-methyl-1H- 223.1 >50 imidazole-4-carboxamide 543 N-((1r,4r)-4-(3- 295.1 >50 aminopropanamido)cyclohexyl)-5-methyl- 4H-1,2,4-triazole-3-carboxamide 544 N-((1r,4r)-4-aminocyclohexyl)-1-methyl-1H- 224.2 >50 1,2,4-triazole-3-carboxamide 545 N-((1r,4r)-4-aminocyclohexyl)-5-chloro-1H- 243.1 >50 pyrazole-3-carboxamide 546 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 311.1 9.76 oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide 547 N-(1-(2-(piperidin-4-yl)acetyl)piperidin-4- 321.2 >50 yl)-4H-1,2,4-triazole-3-carboxamide 548 N-((1r,4r)-4-aminocyclohexyl)-3-iodo-1H- 335.9 >50 1,2,4-triazole-5-carboxamide 549 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-3- 309.2 >50 methyl-1H-1,2,4-triazole-5-carboxamide 550 N-((1r,4r)-4-aminocyclohexyl)-5-methyl-1H- 224.1 14.71 1,2,4-triazole-3-carboxamide 551 N-(1-(1-(L-alanyl)piperidin-4- 362.2 >50 yl)ethyl)thiazolo[5,4-c]pyridine-2- carboxamide 552 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-5- 339.2 6.44 ethylthiazole-2-carboxamide 553 N-((1r,4r)-4-(3- 325.2 25.61 aminopropanamido)cyclohexyl)-5- ethylthiazole-2-carboxamide 554 N-((1r,4r)-4-aminocyclohexyl)-5- 254.1 >50 ethylthiazole-2-carboxamide 555 N-(1-((1r,4r)-4-aminocyclohexane-1- 321.1 >50 carbonyl)piperidin-4-yl)-4H-1,2,4-triazole-3- carboxamide 556 N-(1-(3-aminopropanoyl)piperidin-4-yl)-4H- 267.2 >50 1,2,4-triazole-3-carboxamide 557 (±)-trans-N-(1-(4-aminocyclohexane-1- 344.1 >10 carbonyl)-2-methylpiperidin-4-yl)benzamide 558 (±)-cis-N-(1-(4-aminocyclohexane-1- 358.1 >10 carbonyl)-2-methylpiperidin-4-yl)benzamide (+Na) 559 N-((1r,4r)-4-aminocyclohexyl)-2-oxo-2,3- 275.1 3.49 dihydro-1H-pyrrolo[2,3-c]pyridine-5- carboxamide 560 N-(1-(4-aminobutanoyl)piperidin-4-yl)-4H- 281.1 >10 1,2,4-triazole-3-carboxamide 561 N-((1r,4r)-4-aminocyclohexyl)-N-methyl- 224.1 >10 1H-1,2,4-triazole-5-carboxamide 562 N-((1r,4r)-4-aminocyclohexyl)-4-methyl-1H- 223.2 >10 imidazole-2-carboxamide 563 (±)-trans-N-(1-((3-aminopropyl)sulfonyl)-2- 340.05 >10 methylpiperidin-4-yl)benzamide 564 (±)-cis-N-(1-((3-aminopropyl)sulfonyl)-2- 340.05 >10 methylpiperidin-4-yl)benzamide 565 N-((1r,4r)-4-aminocyclohexyl)-6-bromo-2- 364 >10 hydroxyquinoline-3-carboxamide 566 N-((1r,4r)-4-(3- >10 aminopropanamido)cyclohexyl)-6-bromo-2- hydroxyquinoline-3-carboxamide 567 (±)-cis-N-(1-(4-aminocyclohexane-1- 366.3 >10 carbonyl)-2-methylpiperidin-4-yl)benzamide (+Na) 568 (±)-cis-N-(1-((3-aminopropyl)sulfonyl)-2- 438.15 >10 methylpiperidin-4-yl)-[1,1′,-biphenyl]-4- (+Na) carboxamide 569 (±)-cis-N-(1-((3-aminopropyl)sulfonyl)-2- 368.1 8.02 methylpiperidin-4-yl)-3-ethylbenzamide 570 (±)-cis-N-(1-((3-aminopropyl)sulfonyl)-2- 340.1 >10 methylpiperidin-4-yl)benzamide 571 (±)-trans-N-(1-(4-aminocyclohexane-1- 344.1 >10 carbonyl)-2-methylpiperidin-4-yl)benzamide 572 2-amino-N-((1r,4r)-4-aminocyclohexyl)-1H- 224.1 >10 imidazole-4-carboxamide 573 (±)-trans-N-(1-((3-aminopropyl)sulfonyl)-2- 368.2 >10 methylpiperidin-4-yl)-3-ethylbenzamide 574 N-((1r,4r)-4-aminocyclohexyl)imidazo[1,2- 260.1 >10 a]pyrimidine-3-carboxamide *IC₅₀ values are an average of n = 1 to n = 50

TABLE 3A LCMS M + H or SMYD3 (M + Na) Biochem SMYD3 Cpd. or IC₅₀ cell IC₅₀ No. Chemical Name ((M − NH₂)) (μM)* (μM)* 575 N-((1R,3R,5S)-8-(((1r,4R)-4- 447 0.00044 2.17352 aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 576 N-((1R,3r,5S)-8-((4-aminopiperidin- 466 0.00049 0.52547 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- fluoro-2-oxoindoline-5-carboxamide 577 N-((1R,3r,5S)-8-(((1- 461 0.00067 0.4806 methylpiperidin-4- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 578 N-((1R,3r,5S)-8-((4-aminopiperidin- 448 0.00068 0.85408 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 579 N-((1R,3r,5S)-8-((4-aminopiperidin- 482 0.00081 1.12914 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- chloro-2-oxoindoline-5-carboxamide 580 N-((2S,4S)-1-((4-aminopiperidin-1- 436 0.0009 1.63568 yl)sulfonyl)-2-methylpiperidin-4-yl)- 2-oxoindoline-5-carboxamide 581 N-((1R,3r,5S)-8-(((1-(3- 505 0.00095 1.67455 hydroxypropyl)piperidin-4- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 582 N-((2S,4S)-1-((4-aminopiperidin-1- 470 0.00098 0.81381 yl)sulfonyl)-2-methylpiperidin-4-yl)- 6-chloro-2-oxoindoline-5- carboxamide 583 N-((1R,3R,5S)-8-(((1r,4R)-4- 481 0.0011 1.50735 aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- chloro-2-oxoindoline-5-carboxamide 584 N-((2S)-1-((4-(2-aminopropan-2- 471 0.00147 0.65295 yl)phenyl)sulfonyl)-2- methylpiperidin-4-yl)-2-oxoindoline- 5-carboxamide 585 6-chloro-N-((1R,3r,5S)-8-(((1-(3- 539 0.00173 0.76375 hydroxypropyl)piperidin-4- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 586 6-chloro-N-((1R,3r,5S)-8-((4- 496 0.00189 0.42454 (methylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 587 N-((1R,3r,5S)-8-((4- 538 0.00198 0.07099 (benzylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 588 N-((2S,4S)-1-((4-(2-aminopropan-2- 505 0.00198 0.35648 yl)phenyl)sulfonyl)-2- methylpiperidin-4-yl)-6-chloro-2- oxoindoline-5-carboxamide 589 N-((1R,3r,5S)-8-((4- 462 0.00213 0.98725 (methylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 590 2-oxo-N-((1R,3r,5S)-8-((piperidin-3- 447 0.00214 0.76757 ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 591 N-((1R,3R,5S)-8-(((1s,4S)-4- 447 0.00233 2.31394 aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 592 N-((1R,3r,5S)-8-((4- 572 0.00258 0.05357 (benzylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- chloro-2-oxoindoline-5-carboxamide 593 N-((1R,3r,5S)-8-((4- 476 0.00289 0.50002 (dimethylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 594 6-chloro-N-((1R,3r,5S)-8-((4- 510 0.00346 0.30139 (dimethylamino)piperidin-1- yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 595 6-chloro-2-oxo-N-((1R,3r,5S)-8-(((1- 591 0.00354 0.03609 (4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 596 6-chloro-2-oxo-N-((1R,3r,5S)-8- 481 0.0036 2.66255 ((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 597 2-oxo-N-((1R,3r,5S)-8-((piperidin-4- 447 0.00398 3.43731 ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 598 6-chloro-2-oxo-N-((1R,3S,5S)-8- 481 0.00412 1.26702 ((((S)-piperidin-3- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 599 N-((2S,4S)-2-methyl-1-((piperidin-4- 435 0.00442 9.48804 ylmethyl)sulfonyl)piperidin-4-yl)-2- oxoindoline-5-carboxamide 600 6-chloro-2-oxo-N-((1R,3R,5S)-8- 481 0.00499 0.72841 ((((R)-piperidin-3- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 601 2-oxo-N-((1R,3r,5S)-8-((piperidin-4- 449 0.00521 4.54161 ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2,3- dihydrobenzo[d]oxazole-6- carboxamide 602 N-((1R,3r,5S)-8-((4-aminopiperidin- 528 0.00712 3.72505 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- bromo-2-oxoindoline-5-carboxamide 603 N-((3S)-1-((4-aminopiperidin-1- 470 0.00853 2.67708 yl)sulfonyl)-3-methylpiperidin-4-yl)- 6-chloro-2-oxoindoline-5- carboxamide 604 N-((1R,3r,5S)-8-((4-aminopiperidin- 496 0.01347 0.20704 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- chloro-1-methyl-2-oxoindoline-5- carboxamide 605 N-((2S,4S)-1-((4-aminopiperidin-1- 416 0.01544 0.20068 yl)sulfonyl)-2-methylpiperidin-4-yl)- 5-ethylisothiazole-3-carboxamide 606 N-((1R,3r,5S)-8-((4-aminopiperidin- 462 0.01561 1.79073 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- methyl-2-oxoindoline-5-carboxamide 607 N-((2S,4S)-1-((4-aminopiperidin-1- (451) 0.01813 0.20535 yl)sulfonyl)-2-methylpiperidin-4-yl)- 5-cyclopropyl-1,3,4-thiadiazole-2- carboxamide 608 N-((3R,4R)-1-((4-aminopiperidin-1- 470 0.02137 6.23686 yl)sulfonyl)-3-methylpiperidin-4-yl)- 6-chloro-2-oxoindoline-5- carboxamide 609 N-((1R,3r,5S)-8-((4-aminopiperidin- 464 0.02365 3.70034 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 610 N-((1R,3r,5S)-8-((4-aminopiperidin- 428 0.02378 0.21618 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5- ethylisothiazole-3-carboxamide 611 1-methyl-2-oxo-N-((1R,3r,5S)-8- 461 0.02593 3.91552 ((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 612 N-((1R,3r,5S)-8-((4-(2-aminopropan- 483 0.03068 2.53133 2-yl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 613 N-((1R,3r,5S)-8-((4-(2-aminopropan- 517 0.03712 1.77071 2-yl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6- chloro-2-oxoindoline-5-carboxamide 614 6-chloro-2-oxo-N-((1R,3r,5S)-8-((2- 481 0.04599 0.37965 (pyrrolidin-1-yl)ethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 615 2-oxo-N-((1R,3r,5S)-8-((2- 447 0.04974 0.76121 (pyrrolidin-1-yl)ethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 616 N-((1R,3r,5S)-8-((4-aminopiperidin- 423 0.0499 0.53953 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5- ethylpyridazine-3-carboxamide 617 6-chloro-1-methyl-2-oxo-N- 495 0.05233 2.95866 ((1R,3r,5S)-8-((piperidin-4- ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide 618 N-((1R,3r,5S)-8-((4-aminopiperidin- 441 0.05583 0.3477 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5- cyclopropyl-1,3,4-thiadiazole-2- carboxamide 619 N-((2S,4S)-1-((4-aminopiperidin-1- 411 0.05959 0.46793 yl)sulfonyl)-2-methylpiperidin-4-yl)- 5-ethylpyridazine-3-carboxamide 620 2-oxo-N-(1-((piperidin-4- 421 0.06816 10 ylmethyl)sulfonyl)piperidin-4- yl)indoline-5-carboxamide 621 N-(1-((3- 415 0.07749 6.83658 aminopropyl)sulfonyl)piperidin-4- yl)-6-chloro-2-oxoindoline-5- carboxamide 622 N-((1R,3r,5S)-8-((4- 472 0.13055 1.07968 aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2,2- difluorobenzo[d][1,3]dioxole-5- carboxamide 623 N-((1R,3R,5S)-8-(((1r,4R)-4- 472 0.1358 0.89555 aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2,2- difluorobenzo[d][1,3]dioxole-5- carboxamide 624 N-(1-((3- 381 0.15882 10 aminopropyl)sulfonyl)piperidin-4- yl)-2-oxoindoline-5-carboxamide 625 (R)-2-methyl-3-oxo-N-((1R,3r,5S)-8- 477 0.18459 10 ((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 626 N-((1R,3r,5S)-8-((4-aminopiperidin- 473 0.22228 2.96871 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2,2- difluorobenzo[d][1,3]dioxole-5- carboxamide 627 N-((1R,3R,5S)-8-(((1r,4R)-4- 562 0.22495 1.54162 (benzylamino)cyclohexyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)-2,2- difluorobenzo[d][1,3]dioxole-5- carboxamide 628 2,2-difluoro-N-((1R,3r,5S)-8- 472 0.23189 3.62035 ((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3- yl)benzo[d][1,3]dioxole-5- carboxamide 629 N-((2S,4R)-1-((4-aminopiperidin-1- (438) 0.32589 2.08253 yl)sulfonyl)-2-methylpiperidin-4-yl)- 5-ethylisothiazole-3-carboxamide 630 2,2-difluoro-N-((1R,3r,5S)-8-(((1- 486 0.3614 6.55362 methylpiperidin-4- yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3- yl)benzo[d][1,3]dioxole-5- carboxamide 631 N-((2S,4R)-1-((4-aminopiperidin-1- (451) 0.4699 4.89772 yl)sulfonyl)-2-methylpiperidin-4-yl)- 5-cyclopropyl-1,3,4-thiadiazole-2- carboxamide 632 N-((2S,4S)-1-((4- 471 0.52572 10 acetamidophenyl)sulfonyl)-2- methylpiperidin-4-yl)-2-oxoindoline- 5-carboxamide 633 N-((1R,3r,5S)-8-((4-aminopiperidin- 423 0.52917 10 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5- cyclopropyl-1H-pyrazole-3- carboxamide 634 N-((3R,4S)-1-((4-aminopiperidin-1- 470 0.52937 0.97208 yl)sulfonyl)-3-methylpiperidin-4-yl)- 6-chloro-2-oxoindoline-5- carboxamide 635 3-ethyl-N-((1R,3r,5S)-8-((piperidin- 420 0.62038 10 4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3- yl)benzamide 636 N-((1R,3r,5S)-8-((4-aminopiperidin- 464 0.81894 10 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide 637 N-((1R,3r,5S)-8-((4-aminopiperidin- 423 0.8386 10 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-1- cyclopropyl-1H-pyrazole-4- carboxamide 638 N-((1R,3R,5S)-8-((1r,4R)-4- 411 0.96185 10 aminocyclohexane-1-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide 639 N-((2S,4S)-1-((4-aminopiperidin-1- 411 1.00072 10 yl)sulfonyl)-2-methylpiperidin-4-yl)- 1-cyclopropyl-1H-pyrazole-4- carboxamide 640 N-((2S)-1-((1r,4S)-4- ((416)) 2.04146 10 aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-6-chloro-2- oxoindoline-5-carboxamide 641 N-(1-((4- 491 5.93159 10 acetamidophenyl)sulfonyl)piperidin- 4-yl)-6-chloro-2-oxoindoline-5- carboxamide 642 N-((2S,4S)-1-((1r,4S)-4- ((382)) 6.81095 10 aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-2-oxoindoline- 5-carboxamide 643 N-(1-((4- 457 16.85335 10 acetamidophenyl)sulfonyl)piperidin- 4-yl)-2-oxoindoline-5-carboxamide 644 N-((1R,3r,5S)-8-((4-aminopiperidin-   424.00 0.0185 0.25715 1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-3- cyclopropylisoxazole-5-carboxamide *IC₅₀ values are an average of n = 1 to n = 50

TABLE 4A SMYD2 Biochem Cpd. LCMS IC₅₀ No. Chemical Name M + H (μM)* 645 5-cyclopropyl-N-[1-(propan-2-yl)azetidin-3- 261.2 0.74472 yl]pyridazine-3-carboxamide 646 5-cyclopropyl-N-{1-[(1S)-1-phenylethyl]azetidin-3- 323.2 0.51586 yl}pyridazine-3-carboxamide 647 5-cyclopropyl-N-{1-[(1R)-1-phenylethyl]azetidin-3- 323.2 7.80106 yl}pyridazine-3-carboxamide 648 N-{1-[(5-chloro-1-methyl-1H-imidazol-4- 347.2 7.32825 yl)methyl]azetidin-3-yl}-5-cyclopropylpyridazine-3- carboxamide 649 5-cyclopropyl-N-{1-[1-(2,5- 391.1 0.14034 dichlorophenyl)ethyl]azetidin-3-yl}pyridazine-3- carboxamide 650 5-cyclopropyl-N-(1-{1-[3-(2-hydroxyethoxy)-2- 413.2 0.31235 methoxyphenyl]ethyl}azetidin-3-yl)pyridazine-3- carboxamide 651 N-(1-benzylazetidin-3-yl)-5-cyclopropylpyridazine- 309.2 0.54112 3-carboxamide 652 N-(1-{1-[2-chloro-3-(2- 417.2 0.04156 hydroxyethoxy)phenyl]ethyl}azetidin-3-yl)-5- cyclopropylpyridazine-3-carboxamide 657 N-(azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4- 208.1 10.38816 carboxamide 659 1-cyclopropyl-N-(1-methylazetidin-3-yl)-1H-1,2,3- 222.1 2.8375 triazole-4-carboxamide 660 1-cyclopropyl-N-(1-propylazetidin-3-yl)-1H-1,2,3- 250.1 1.16661 triazole-4-carboxamide 661 1-cyclopropyl-N-(1-ethylazetidin-3-yl)-1H-1,2,3- 236.2 1.57571 triazole-4-carboxamide 662 1-cyclopropyl-N-[1-(propan-2-yl)azetidin-3-yl]-1H- 250.2 0.84606 1,2,3-triazole-4-carboxamide 663 1-cyclopropyl-N-[1-(propan-2-yl)azetidin-3-yl]-1H- 250.2 0.58519 1,2,3-triazole-4-carboxamide 664 1-cyclopropyl-N-(1-cyclopropylazetidin-3-yl)-1H- 248.1 1.48071 1,2,3-triazole-4-carboxamide 665 1-cyclopropyl-N-[1-(cyclopropylmethyl)azetidin-3- 262.2 1.99933 yl]-1H-1,2,3-triazole-4-carboxamide 666 1-cyclopropyl-N-[1-(oxetan-3-ylmethyl)azetidin-3- 278.2 6.06091 yl]-1H-1,2,3-triazole-4-carboxamide 667 1-cyclopropyl-N-[1-(2-methoxyethyl)azetidin-3-yl]- 266.2 2.45794 1H-1,2,3-triazole-4-carboxamide 668 1-cyclopropyl-N-[1-(2-methylpropyl)azetidin-3-yl]- 264.2 2.74698 1H-1,2,3-triazole-4-carboxamide 669 N-[1-(cyclobutylmethyl)azetidin-3-yl]-1- 276.2 1.61707 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 670 1-cyclopropyl-N-[1-(2-hydroxyethyl)azetidin-3-yl]- 252.1 4.53271 1H-1,2,3-triazole-4-carboxamide 671 N-(1-benzylazetidin-3-yl)-1-cyclopropyl-1H-1,2,3- 298.1 4.20527 triazole-4-carboxamide 672 N-(1-benzylazetidin-3-yl)-1-cyclopropyl-1H-1,2,3- 298.2 1.55139 triazole-4-carboxamide 673 1-cyclopropyl-N-[1-(2-phenylethyl)azetidin-3-yl]- 312.2 1.55399 1H-1,2,3-triazole-4-carboxamide 674 1-cyclopropyl-N-[1-(2-hydroxy-1- 328.2 4.27205 phenylethyl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 675 1-cyclopropyl-N-[1-(1-phenylpropyl)azetidin-3-yl]- 326.2 0.49364 1H-1,2,3-triazole-4-carboxamide 676 N-{1-[1-(4-chlorophenyl)ethyl]azetidin-3-yl}-1- 346.2 2.18182 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 677 1-cyclopropyl-N-{1-[1-(2,4- 348.2 2.86259 difluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 678 1-cyclopropyl-N-{1-[1-(2- 330.2 0.90683 fluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole- 4-carboxamide 679 1-cyclopropyl-N-{1-[1-(3- 342.2 1.45146 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 680 1-cyclopropyl-N-(1-{1-[4- 380.2 >50.0 (trifluoromethyl)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 681 N-{1-[1-(4-butoxyphenyl)ethyl]azetidin-3-yl}-1- 384.2 1.29111 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 682 1-cyclopropyl-N-{1-[1-(2- 342.3 0.66494 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 683 1-cyclopropyl-N-{1-[1-(2- 342.3 0.79678 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 684 1-cyclopropyl-N-(1-{1-[2- 396.2 2.13234 (trifluoromethoxy)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 685 1-cyclopropyl-N-{1-[1-(pyridin-2-yl)ethyl]azetidin- 313.1 3.56033 3-yl}-1H-1,2,3-triazole-4-carboxamide 686 1-cyclopropyl-N-[1-(3-methoxypropyl)azetidin-3- 280.1 3.76161 yl]-1H-1,2,3-triazole-4-carboxamide 687 1-cyclopropyl-N-{1-[1-(3,4- 348.2 2.89677 difluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 688 1-cyclopropyl-N-{1-[1-(3,4- 386.2 5.09675 dimethoxyphenyl)propan-2-yl]azetidin-3-yl}-1H- 1,2,3-triazole-4-carboxamide 689 1-cyclopropyl-N-{1-[1-(4-fluoro-2- 360.2 1.88646 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 690 1-cyclopropyl-N-(1-{1-[2-methoxy-5- 410.2 7.98548 (trifluoromethyl)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 691 N-{1-[1-(2H-1,3-benzodioxol-5-yl)ethyl]azetidin-3- 356.2 0.80698 yl}-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 692 N-(1-{1-[4-(benzyloxy)phenyl]ethyl}azetidin-3-yl)- 418.2 0.17228 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 693 N-(1-{1-[4-(benzyloxy)phenyl]ethyl}azetidin-3-yl)- 418.3 0.17574 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 694 1-cyclopropyl-N-{1-[1-(4- 344.2 0.78735 fluorophenyl)propyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 695 N-{1-[1-(3-chlorophenyl)ethyl]azetidin-3-yl}-1- 346.1 1.00761 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 696 1-cyclopropyl-N-{1-[1-(2,5- 380.1 0.18717 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 697 1-cyclopropyl-N-{1-[1-(2,5- 380.1 0.18937 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 698 1-cyclopropyl-N-{1-[1-(3,4- 372.2 3.69446 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 699 1-cyclopropyl-N-{1-[1-(pyrimidin-5- 314.2 9.54128 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 700 1-cyclopropyl-N-(1-{1-[4- 394.2 2.66609 (trifluoromethyl)phenyl]propyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 701 1-cyclopropyl-N-(1-{[3-(2- 372.2 8.02678 methoxyethoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 702 1-cyclopropyl-N-(1-{1-[3-(2- 386.1 3.57947 methoxyethoxy)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 703 1-(2-hydroxyethyl)-N-[1-(propan-2-yl)azetidin-3- 254.2 >50.0 yl]-1H-1,2,3-triazole-4-carboxamide 704 1-cyclopropyl-N-(1-{1-[3-(2- 372.2 0.64045 hydroxyethoxy)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 705 1-cyclopropyl-N-[1-(1-{3-[2- 385.2 2.04485 (methylamino)ethoxy]phenyl}ethyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 706 1-cyclopropyl-N-[1-(1-{3-[2- 399.2 2.1244 (dimethylamino)ethoxy]phenyl}ethyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 707 1-cyclopropyl-N-[1-(3-hydroxypropyl)azetidin-3- 266.1 1.91172 yl]-1H-1,2,3-triazole-4-carboxamide 708 1-cyclopropyl-N-{1-[3- 293.2 >50.0 (dimethylamino)propyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 709 1-cyclopropyl-N-{1-[(1S)-1-phenylethyl]azetidin-3- 312.2 0.37665 yl}-1H-1,2,3-triazole-4-carboxamide 710 N-{1-[1-(2-chloro-4-fluorophenyl)ethyl]azetidin-3- 364.1 0.34116 yl}-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 711 1-cyclopropyl-N-{1-[1-(3- 344.2 1.00729 fluorophenyl)propyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 712 N-(1-{1-[4-chloro-3- 414.2 7.35557 (trifluoromethyl)phenyl]ethyl}azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 713 N-[1-(4-chloro-5-methoxy-2,3-dihydro-1H-inden-1- 388.1 12.88746 yl)azetidin-3-yl]-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 714 N-{1-[1-(3-chloro-5-fluorophenyl)ethyl]azetidin-3- 364.1 2.12503 yl}-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 715 1-cyclopropyl-N-{1-[1-(pyrimidin-2- 314.2 1.9389 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 716 1-cyclopropyl-N-{1-[1-(1,3-thiazol-2- 319.1 30.73955 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 717 1-cyclopropyl-N-(1-{[1-(2-methoxyethyl)-1H- 346.3 3.05744 pyrazol-4-yl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 718 1-cyclopropyl-N-{1-[1-(dimethyl-1,3-thiazol-5- 347.2 2.95156 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 719 N-[1-(5-chloro-2,3-dihydro-1H-inden-1-yl)azetidin- 358.2 4.40844 3-yl]-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 720 1-cyclopropyl-N-{1-[(1R)-1-phenylethyl]azetidin-3- 312.2 23.25339 yl}-1H-1,2,3-triazole-4-carboxamide 721 1-cyclopropyl-N-{1-[(1R)-1-phenylpropyl]azetidin- 326.2 4.80835 3-yl}-1H-1,2,3-triazole-4-carboxamide 722 1-cyclopropyl-N-{1-[(1S)-1-phenylpropyl]azetidin- 326.3 0.19827 3-yl}-1H-1,2,3-triazole-4-carboxamide 723 1-(2-aminoethyl)-N-[1-(propan-2-yl)azetidin-3-yl]- 253.2 >50.0 1H-1,2,3-triazole-4-carboxamide 724 1-cyclopropyl-N-{1-[1-(4-methoxypyridin-2- 343.2 1.27222 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 725 1-cyclopropyl-N-{1-[1-(3-methoxypyridin-2- 343.2 1.02479 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 726 1-cyclopropyl-N-(1-{[3- 355.2 10.70724 (methylcarbamoyl)phenyl]methyl}azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 727 N-{1-[(3-carbamoylphenyl)methyl]azetidin-3-yl}-1- 341.1 7.29596 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 728 1-cyclopropyl-N-(1-{1-[4-(morpholin-4- 397.2 0.75494 yl)phenyl]ethyl}azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 729 1-cyclopropyl-N-{1-[2,2,2-trifluoro-1-(3- 396.2 >50.0 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 730 1-cyclopropyl-N-{1-[1-(3- 404.2 3.04417 phenoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 731 N-{1-[cyclobutyl(phenyl)methyl]azetidin-3-yl}-1- 352.2 1.51599 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 732 1-cyclopropyl-N-{1-[1-(4-fluoro-3- 360.2 2.58965 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 733 1-cyclopropyl-N-{1-[(1-methyl-1H-imidazol-4- 302.2 6.80081 yl)methyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 734 1-cyclopropyl-N-(1-{[3-(2- 358.2 2.30886 hydroxyethoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 735 1-cyclopropyl-N-[1-({3-[2- 371.2 2.33404 (methylamino)ethoxy]phenyl}methyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 736 1-cyclopropyl-N-[1-({3-[2- 385.2 2.80792 (dimethylamino)ethoxy]phenyl}methyl)azetidin-3- yl]-1H-1,2,3-triazole-4-carboxamide 737 N-(1-{1-[3-(benzyloxy)phenyl]ethyl}azetidin-3-yl)- 418.3 0.71843 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 738 1-cyclopropyl-N-[1-(5-methoxy-1,2,3,4- 368.3 5.82879 tetrahydronaphthalen-1-yl)azetidin-3-yl]-1H-1,2,3- triazole-4-carboxamide 739 1-cyclopropyl-N-{1-[1-(4- 404.2 1.07309 phenoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 740 1-cyclopropyl-N-[1-(5-fluoro-2,3-dihydro-1H-inden- 342.2 6.96336 1-yl)azetidin-3-yl]-1H-1,2,3-triazole-4-carboxamide 741 1-cyclopropyl-N-(1-{1-[2- 380.2 1.00727 (trifluoromethyl)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 742 1-cyclopropyl-N-{1-[1-(2,6- 348.2 2.84963 difluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 743 1-cyclopropyl-N-{1-[1-(2,3- 380.2 0.48846 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 744 1-cyclopropyl-N-[1-(4,5-dimethoxy-2,3-dihydro- 384.2 23.71632 1H-inden-1-yl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 745 1-cyclopropyl-N-{1-[1-(pyrazin-2-yl)ethyl]azetidin- 314.1 7.44095 3-yl}-1H-1,2,3-triazole-4-carboxamide 746 1-cyclopropyl-N-{1-[1-(2,5- 348.2 7.77636 difluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 747 1-cyclopropyl-N-{1-[1-(4- 330.2 1.92161 fluorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole- 4-carboxamide 748 1-cyclopropyl-N-(1-{1-[3- 380.2 2.80977 (trifluoromethyl)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 749 1-cyclopropyl-N-{1-[2,2,2-trifluoro-1-(4- 396.1 0.56478 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 750 1-cyclopropyl-N-{1-[1-(2-hydroxy-6- 358.2 1.27817 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 751 1-cyclopropyl-N-{1-[1-(1,3-thiazol-2- 333.2 20.98439 yl)propyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 752 1-cyclopropyl-N-[1-(2-methoxy-1- 342.2 6.09419 phenylethyl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 753 1-cyclopropyl-N-[1-({3- 341.3 15.98565 [(methylamino)methyl]phenyl}methyl)azetidin-3- yl]-1H-1,2,3-triazole-4-carboxamide 754 N-(1-{[3-(aminomethyl)phenyl]methyl}azetidin-3- 327.2 7.33653 yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 755 1-cyclopropyl-N-[1-(1-phenylcyclopropyl)azetidin- 324.2 30.45617 3-yl]-1H-1,2,3-triazole-4-carboxamide 756 1-cyclopropyl-N-[1-({1-[2-(methylamino)ethyl]-2- 362.3 17.04064 oxopyrrolidin-3-yl}methyl)azetidin-3-yl]-1H-1,2,3- triazole-4-carboxamide 757 1-cyclopropyl-N-[1-(2-phenylpropan-2-yl)azetidin- 326.2 3.8847 3-yl]-1H-1,2,3-triazole-4-carboxamide 758 1-cyclopropyl-N-(1-{[4-(methylamino)oxan-2- 335.3 >50.0 yl]methyl}azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 759 1-cyclopropyl-N-[1-(1-phenylpropan-2-yl)azetidin- 326.2 1.39034 3-yl]-1H-1,2,3-triazole-4-carboxamide 760 1-cyclopropyl-N-{1-[1-(4-fluorophenyl)-2- 358.2 3.27451 methylpropyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 761 1-cyclopropyl-N-{1-[1-(1H-indazol-3- 352.2 3.21089 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 762 1-cyclopropyl-N-[1-(7-methoxy-2,3-dihydro-1H- 354.3 7.97221 inden-1-yl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 763 1-cyclopropyl-N-{1-[1-(2,3- 372.2 0.08855 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 764 1-cyclopropyl-N-{1-[1-(2,3- 372.2 0.09346 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 765 1-cyclopropyl-N-{1-[(3-oxo-2,3-dihydro-1H- 353.1 10.21303 isoindol-5-yl)methyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 766 1-cyclopropyl-N-[1-(2,2,2-trifluoro-1- 366.2 >50.0 phenylethyl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 767 1-cyclopropyl-N-{1-[1-(2,3-dihydro-1,4- 370.1 0.57587 benzodioxin-6-yl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 768 1-cyclopropyl-N-{1-[1-(2,6- 372.3 1.68248 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 769 1-cyclopropyl-N-{1-[1-(2,6- 380.1 1.19872 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 770 1-(2,2-difluorocyclopropyl)-N-[1-(propan-2- 286.2 4.19117 yl)azetidin-3-yl]-1H-1,2,3-triazole-4-carboxamide 771 1-cyclopropyl-N-[1-(1-{3- 355.2 4.98252 [(methylamino)methyl]phenyl}ethyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 772 1-cyclopropyl-N-(1-{[3-(hydroxymethyl)-2- 358.2 10.81324 methoxyphenyl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 773 1-cyclopropyl-N-[1-(2-methanesulfonyl-1- 390.1 >50.0 phenylethyl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 774 1-cyclopropyl-N-{1-[1-(3-oxo-3,4-dihydro-2H-1,4- 383.2 1.61549 benzoxazin-6-yl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 775 N-(1-{1-[2-chloro-3-(2- 406.2 0.04944 hydroxyethoxy)phenyl]ethyl}azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 776 1-cyclopropyl-N-(1-{1-[3-(2-hydroxyethoxy)-2- 402.2 0.34533 methoxyphenyl]ethyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 777 1-cyclopropyl-N-{1-[(3-methoxy-1-methyl-1H- 332.2 5.61969 pyrazol-4-yl)methyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 778 rel-N-{1-[(1R)-1-[4- 418.2 0.08453 (benzyloxy)phenyl]ethyl]azetidin-3-yl}-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 779 rel-1-cyclopropyl-N-{1-[(1R)-1-(2,5- 380.1 0.10953 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 780 rel-1-cyclopropyl-N-{1-[(1R)-1-(2- 342.3 0.3468 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 781 1-cyclopropyl-N-[1-(3-phenyloxetan-3-yl)azetidin- 340.2 >50.0 3-yl]-1H-1,2,3-triazole-4-carboxamide 782 1-cyclopropyl-N-(1-{[1-(2-phenylethyl)-1H- 392.4 2.61584 imidazol-4-yl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 783 1-cyclopropyl-N-{1-[1-(3- 369.1 3.13518 acetamidophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 784 N-{1-[(5-chloro-1-methyl-1H-imidazol-4- 336.2 21.02524 yl)methyl]azetidin-3-yl}-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 785 1-cyclopropyl-N-{1-[1-(1H-imidazol-4- 302.2 2.594 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 786 1-cyclopropyl-N-{1-[cyclopropyl(4- 356.1 1.70115 fluorophenyl)methyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 787 1-cyclopropyl-N-[1-(2-methyl-1- 340.3 1.42952 phenylpropyl)azetidin-3-yl]-1H-1,2,3-triazole-4- carboxamide 788 rel-N-{1-[(1R)-1-[4- 0.4137 (benzyloxy)phenyl]ethyl]azetidin-3-yl}-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 789 rel-1-cyclopropyl-N-{1-[(1R)-1-(2,5- 31.57011 dichlorophenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 790 rel-1-cyclopropyl-N-{1-[(1R)-1-(2- 28.78884 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 791 1-cyclopropyl-N-{1-[1-(pyridin-2- 327.1 2.47462 yl)propyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 792 N-{1-[(1-benzyl-1H-pyrazol-4-yl)methyl]azetidin-3- 378.2 0.01635 yl}-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 793 1-cyclopropyl-N-[1-(6-methoxy-1,2,3,4- 368.2 9.91987 tetrahydronaphthalen-1-yl)azetidin-3-yl]-1H-1,2,3- triazole-4-carboxamide 794 N-(1-{[3-(aminomethyl)-2- 357.3 32.30456 methoxyphenyl]methyl}azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 795 N-{1-[(1-benzyl-1H-imidazol-4-yl)methyl]azetidin- 378.3 7.14819 3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 796 N-(1-{1-[2-(benzyloxy)phenyl]ethyl}azetidin-3-yl)- 418.2 0.4215 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 797 1-cyclopropyl-N-(1-{1-[4-(1H-imidazol-1- 378.1 1.56764 yl)phenyl]ethyl}azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 798 1-cyclopropyl-N-{1-[1-(2- 344.2 0.42506 fluorophenyl)propyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 799 1-cyclopropyl-N-[2,2-dimethyl-1-(propan-2- 278.2 9.59545 yl)azetidin-3-yl]-1H-1,2,3-triazole-4-carboxamide 800 N-(1-{1-[4-(benzyloxy)-2- 448.3 0.96532 methoxyphenyl]ethyl}azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4-carboxamide 801 1-cyclopropyl-N-{1-[1-(2,4- 372.3 1.05608 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 802 N-(1-{[4-(benzyloxy)phenyl]methyl}azetidin-3-yl)- 404.2 0.08341 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 803 N-{1-[1-(2-chloro-3-methoxyphenyl)ethyl]azetidin- 376.2 0.06945 3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 804 rel-1-cyclopropyl-N-{1-[(1R)-1-(2,3- 372.2 0.04426 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 805 rel-1-cyclopropyl-N-{1-[(1S)-1-(2,3- 42.35178 dimethoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 806 1-cyclopropyl-N-(1-{[1-(2-phenylethyl)-1H-pyrazol- 392.2 0.97043 4-yl]methyl}azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 807 5-cyclopropyl-N-(1-{[1-(2-phenylethyl)-1H-pyrazol- 403.2 0.52752 4-yl]methyl}azetidin-3-yl)pyridazine-3-carboxamide 808 1-cyclopropyl-N-[1-(propan-2-yl)piperidin-3-yl]- 278.2 19.78446 1H-1,2,3-triazole-4-carboxamide 809 N-{1-[(1-benzyl-1H-imidazol-5-yl)methyl]azetidin- 378.3 >50.0 3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 810 1-cyclopropyl-N-(1-{[1-(2-phenylethyl)-1H- 392.3 9.28801 imidazol-5-yl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 811 N-{1-[(3-chloro-1-methyl-1H-pyrazol-4- 336.1 1.2247 yl)methyl]azetidin-3-yl}-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 812 1-cyclopropyl-N-[1-({2-methoxy-3- 371.2 41.20464 [(methylamino)methyl]phenyl}methyl)azetidin-3- yl]-1H-1,2,3-triazole-4-carboxamide 813 1-cyclopropyl-N-{1-[1-(4-fluorophenyl)-2- 346.2 15.19205 hydroxyethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 814 5-cyclopropyl-N-(1-ethylazetidin-3-yl)pyridazine-3- 247.2 0.59765 carboxamide 815 5-cyclopropyl-N-[1-(propan-2-yl)piperidin-3- 289.2 18.67277 yl]pyridazine-3-carboxamide 816 N-(1-{1-[4-(benzyloxy)phenyl]-2,2,2- 472.3 >50.0 trifluoroethyl}azetidin-3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 817 N-(1-{1-[4-(benzyloxy)-2- 452.2 0.10155 chlorophenyl]ethyl}azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4-carboxamide 818 1-cyclopropyl-N-(1-{[4-(3- 386.3 3.00034 methoxypropoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 819 1-cyclopropyl-N-(1-{[4-(2,3- 388.2 1.99348 dihydroxypropoxy)phenyl]methyl}azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 820 N-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4- 320 >50.0 benzoxazin-7-yl)-3-(methylamino)cyclohexane-1- carboxamide 821 1-cyclopropyl-N-{1-[1-(4- 342.3 0.78452 methoxyphenyl)ethyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 822 1-cyclopropyl-N-(1-{[4-(2- 372.3 1.96551 hydroxypropoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 823 1-cyclopropyl-N-(1-{[4-(3- 372.2 3.21621 hydroxypropoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 824 1-cyclopropyl-N-{1-[(4- 314.1 0.88212 hydroxyphenyl)methyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 825 5-cyclopropyl-N-(1-methylazetidin-3-yl)pyridazine- 233.2 0.39067 3-carboxamide 826 1-cyclopropyl-N-{1-[(4- 328.2 1.83875 methoxyphenyl)methyl]azetidin-3-yl}-1H-1,2,3- triazole-4-carboxamide 827 1-cyclopropyl-N-(1-{[4-(2- 358.3 1.37605 hydroxyethoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 828 1-cyclopropyl-N-(1-{[4-(pyridin-4- 405.2 1.03298 ylmethoxy)phenyl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 829 1-cyclopropyl-N-[1-(1-(4-[2-(morpholin-4-yl)-2- 455.3 0.71252 oxoethoxy]phenyl}ethyl)azetidin-3-yl]-1H-1,2,3- triazole-4-carboxamide 830 1-cyclopropyl-N-(1-{[4-(2- 372.3 2.06713 methoxyethoxy)phenyl]methyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 831 rel-N-{1-[(1S)-1-[2-chloro-3-(2- 406.2 0.05775 hydroxyethoxy)phenyl]ethyl]azetidin-3-yl}-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 832 rel-N-{1-[(1R)-1-[2-chloro-3-(2- 406.2 14.28102 hydroxyethoxy)phenyl]ethyl]azetidin-3-yl}-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 833 N-{1-[(3-chloro-1-methyl-1H-pyrazol-4- 347.1 0.94017 yl)methyl]azetidin-3-yl}-5-cyclopropylpyridazine-3- carboxamide 834 1-cyclopropyl-N-[2-(dimethylamino)ethyl]-1H- 224.3 >50.0 1,2,3-triazole-4-carboxamide 835 1-cyclopropyl-N-[1-(1-(2-methoxy-3- 385.3 0.77956 [(methylamino)methyl]phenyl}ethyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 836 N-(1-{1-[4-(benzyloxy)phenyl]ethyl}azetidin-3-yl)- 429.3 0.02651 5-cyclopropylpyridazine-3-carboxamide 837 N-{1-[(1S)-1-(3-chlorophenyl)propyl]azetidin-3-yl}- 360.3 0.33977 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 838 5-cyclopropyl-N-(1-{[1-(2-phenylethyl)-1H- 403.3 0.49607 imidazol-4-yl]methyl}azetidin-3-yl)pyridazine-3- carboxamide 839 N-[1-(azetidin-3-yl)ethyl]-5-cyclopropylpyridazine- 247.2 18.24266 3-carboxamide 840 5-cyclopropyl-N-{1-[1-(propan-2-yl)azetidin-3- 289.2 36.83929 yl]ethyl}pyridazine-3-carboxamide 841 5-cyclopropyl-N-{1-[(1S)-1-(2- 353.3 5.00737 methoxyphenyl)ethyl]azetidin-3-yl}pyridazine-3- carboxamide 842 5-cyclopropyl-N-{1-[(1R)-1-(2- 353.3 0.18913 methoxyphenyl)ethyl]azetidin-3-yl}pyridazine-3- carboxamide 843 (±)-cis-N-(1-{[3- 382.2 1.15555 (benzyloxy)cyclobutyl]methyl}azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 844 1-cyclopropyl-N-[1-(1-{4-[2-oxo-2-(piperidin-1- 453.3 1.54771 yl)ethoxy]phenyl}ethyl)azetidin-3-yl]-1H-1,2,3- triazole-4-carboxamide 845 N-{1-[1-(2-chloro-4-methoxyphenyl)ethyl]azetidin- 376.2 0.08798 3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 846 1-cyclopropyl-N-(1-{[4-(1,3-thiazol-4- 411.2 1.08508 ylmethoxy)phenyl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 847 N-[1-(1-{4-[(3- 452.2 0.27389 chlorophenyl)methoxy]phenyl}ethyl)azetidin-3-yl]- 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 848 N-[1-(1-{4-[(4- 452.2 0.06933 chlorophenyl)methoxy]phenyl}ethyl)azetidin-3-yl]- 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 849 1-cyclopropyl-N-(1-{[4-(pyridin-2- 405.1 2.66119 ylmethoxy)phenyl]methyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 850 1-cyclopropyl-N-(1-{1-[4-(piperidin-3- 425.2 3.32842 ylmethoxy)phenyl]ethyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 851 N-{1-[1-(2-chloro-3-methoxyphenyl)ethyl]azetidin- 387.2 0.07206 3-yl}-5-cyclopropylpyridazine-3-carboxamide 852 (±)-trans-N-(1-{[3- 382.3 0.98162 (benzyloxy)cyclobutyl]methyl}azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 853 1-cyclopropyl-N-(1-{1-[4-(2- 432.3 0.77613 phenylethoxy)phenyl]ethyl}azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 854 1-cyclopropyl-N-{1-[1-(4-{[4- 475.3 0.96536 (methylcarbamoyl)phenyl]methoxy}phenyl)eth- yl]azetidin-3-yl}-1H-1,2,3-triazole-4-carboxamide 855 1-cyclopropyl-N-[1-(1-{4-[(4- 448.3 0.15904 methoxyphenyl)methoxy]phenyl}ethyl)azetidin-3- yl]-1H-1,2,3-triazole-4-carboxamide 856 5-cyclopropyl-N-{1-[1-(4- 353.2 0.60267 methoxyphenyl)ethyl]azetidin-3-yl}pyridazine-3- carboxamide 857 1-cyclopropyl-N-[1-(1-{4-[2- 399.2 1.97865 (dimethylamino)ethoxy]phenyl}ethyl)azetidin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 858 1-cyclopropyl-N-[1-(1-{4-[3- 413.2 4.79409 (dimethylamino)propoxy]phenyl}ethyl)azetidin-3- yl]-1H-1,2,3-triazole-4-carboxamide 859 N-{1-[1-(2-chlorophenyl)ethyl]azetidin-3-yl}-1- 346.2 0.16007 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 860 N-{1-[1-(5-chloro-2-methoxyphenyl)ethyl]azetidin- 376.2 2.79163 3-yl}-1-cyclopropyl-1H-1,2,3-triazole-4- carboxamide 861 5-cyclopropyl-N-{1-[1-(2,3- 383.2 0.12148 dimethoxyphenyl)ethyl]azetidin-3-yl}pyridazine-3- carboxamide 862 N-(1-{1-[4-(benzylamino)phenyl]ethyl}azetidin-3- 417.3 0.334 yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 863 N-{1-[1-(4-benzamidophenyl)ethyl]azetidin-3-yl}-1- 431.3 1.73815 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 864 1-cyclopropyl-N-(1-{1-[4-(2,2- 398.3 3.14078 dimethylpropoxy)phenyl]ethyl}azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 865 1-cyclopropyl-N-{1-[1-(5-methoxypyrimidin-2- 344.2 1.6379 yl)ethyl]azetidin-3-yl}-1H-1,2,3-triazole-4- carboxamide 866 N-{1-[(1S)-1-(3-chlorophenyl)propyl]azetidin-3-yl}- 371.2 0.35518 5-cyclopropylpyridazine-3-carboxamide 867 5-cyclopropyl-N-[3- 249.2 >50.0 (dimethylamino)propyl]pyridazine-3-carboxamide 868 N-(1-{1-[4-(benzyloxy)-3- 452.2 0.92507 chlorophenyl]ethyl}azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4-carboxamide 869 5-cyclopropyl-N-[2- 235.2 21.10972 (dimethylamino)ethyl]pyridazine-3-carboxamide 913 5-cyclopropyl-N-[1-(propan-2-yl)azetidin-3-yl]-1H- 249.2 1.69797 imidazole-2-carboxamide 914 5-cyclopropyl-N-{1-[(1S)-1-phenylethyl]azetidin-3- 311.2 0.72872 yl}-1H-imidazole-2-carboxamide 915 5-cyclopropyl-N-{1-[(1R)-1-phenylethyl]azetidin-3- 311.2 >50.0 yl}-1H-imidazole-2-carboxamide 916 5-cyclopropyl-N-[1-(propan-2-yl)piperidin-4- 289.3 29.10492 yl]pyridazine-3-carboxamide 917 5-cyclopropyl-N-(1-methylpiperidin-4- 261.2 >50.0 yl)pyridazine-3-carboxamide 918 5-cyclopropyl-N-(1-methylpiperidin-3- 261.3 >50.0 yl)pyridazine-3-carboxamide *IC₅₀ values are an average of n = 1 to n = 50

TABLE 6A SMYD2 Biochem Cpd. LCMS IC₅₀ No. Chemical Name M + H (μM)* 919 1-cyclopropyl-N-(1-isopropylazetidin-3-yl)-1H- 249.2 4.6 imidazole-4-carboxamide 920 N-(1-(1-(3-(2-chlorophenyl)-1H-indazol-5- 462.2 >50 yl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 921 1-cyclopropyl-N-(3-(dimethylamino)propyl)-1H- 238.3 5.4 1,2,3-triazole-4-carboxamide 922 1-cyclopropyl-N-(1-(1-(4- 417.2 0.65 ((phenylamino)methyl)phenyl)ethyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 923 1-cyclopropyl-N-(1-(1-(5-methoxypyridin-2- 343.3 2.7 yl)ethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 924 1-cyclopropyl-N-(1-((6-(phenylamino)pyridin-3- 390.2 yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 925 1-cyclopropyl-N-(1-(1-(4-(piperidin-4- 425.3 4.3 ylmethoxy)phenyl)ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 926 N-(1-((6-(benzylamino)pyridin-3-yl)methyl)azetidin- 404.2 3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 927 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 411.2 0.011 yl)methyl)azetidin-3-yl)-4-cyclopropyl-1H- imidazole-2-carboxamide 928 5-cyclopropyl-N-(1-(4-((1-methyl-1H-pyrazol-4- 419.3 0.61 yl)methoxy)benzyl)azetidin-3-yl)pyridazine-3- carboxamide 929 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 423.2 0.0012 yl)methyl)azetidin-3-yl)-5-cyclopropylpyridazine-3- carboxamide 930 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 422.7 0.0033 yl)methyl)azetidin-3-yl)-4-cyclopropylpicolinamide 931 N-(1-((1-benzyl-1H-1,2,3-triazol-4- 379.3 11.1 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 932 1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H- 408.2 0.028 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 933 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 389.2 0.0078 yl)-5-cyclopropylpyridazine-3-carboxamide 934 5-cyclopropyl-N-(1-(1-(3- 353.2 0.69 methoxyphenyl)ethyl)azetidin-3-yl)pyridazine-3- carboxamide 935 1-cyclopropyl-N-(1-(1-(2-methyl-2H-indazol-5- 366.2 1.6 yl)ethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 936 N-(1-((1-(benzo[d]thiazol-5-ylmethyl)-1H-pyrazol-4- 435.2 0.080 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 937 1-cyclopropyl-N-(1-((1-((4-methyloxazol-2- 383.2 0.12 yl)methyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 938 N-(1-(1-(2-chloro-5-methoxyphenyl)ethyl)azetidin- 376.2 0.13 3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 939 N-(1-(1-(4-(benzyloxy)-3- 448.3 3.6 methoxyphenyl)ethyl)azetidin-3-yl)-1-cyclopropyl- 1H-1,2,3-triazole-4-carboxamide 940 N-(1-((1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1- 288.2 7.7 cyclopropyl-1H-1,2,3-triazole-4-carboxamide 941 1-cyclopropyl-N-(1-((1-(4-(methylthio)benzyl)-1H- 424.2 0.028 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 942 N-(1-((1-(2-chlorobenzyl)-1H-pyrazol-4- 412.1 0.11 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 943 1-cyclopropyl-N-(1-((1-(4-(trifluoromethyl)benzyl)- 446.2 0.014 1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 944 1-cyclopropyl-N-(1-((1-(oxazol-2-ylmethyl)-1H- 369.2 0.92 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 945 1-cyclopropyl-N-(1-((1-(thiazol-4-ylmethyl)-1H- 385.2 1.2 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 946 1-cyclopropyl-N-(1-((1-ethyl-1H-pyrazol-4- 316.2 2.0 yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 947 N-(1-((1-(4-(tert-butyl)benzyl)-1H-pyrazol-4- 434.3 0.056 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 948 N-(1-((1-(cyclohexylmethyl)-1H-pyrazol-4- 384.3 0.36 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 949 1-cyclopropyl-N-(1-((1-((tetrahydro-2H-pyran-4- 386.2 2.4 yl)methyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 950 1-cyclopropyl-N-(1-((1-((tetrahydrofuran-3- 372.3 2.0 yl)methyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 951 1-cyclopropyl-N-(1-((1-(4-fluorobenzyl)-1H-pyrazol- 396.2 0.022 4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 952 1-cyclopropyl-N-(1-(1-(1-methyl-1H-indazol-5- 366.2 1.63 yl)ethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 953 N-(1-(4-((1H-pyrazol-1-yl)methyl)benzyl)azetidin-3- 378.3 5.6 yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 954 N-(1-(4-((1H-pyrazol-1-yl)methyl)benzyl)azetidin-3- 389.3 2.4 yl)-5-cyclopropylpyridazine-3-carboxamide 955 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 378.2 0.073 yl)-5-cyclopropylisoxazole-3-carboxamide 956 N-(1-(1-(2-chloro-3-(2-hydroxy-2- 434.2 2.6 methylpropoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 957 1-cyclopropyl-N-(1-(1-(4-((4- 448.3 0.16 methoxybenzyl)oxy)phenyl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 958 5-cyclopropyl-N-(1-(1-(4- 353.2 0.60 methoxyphenyl)ethyl)azetidin-3-yl)pyridazine-3- carboxamide 959 1-cyclopropyl-N-(1-(1-(4-(2- 399.2 2.0 (dimethylamino)ethoxy)phenyl)ethyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 960 1-cyclopropyl-N-(1-(1-(4- 432.3 0.78 phenethoxyphenyl)ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 961 4-cyclopropyl-N-(1-isopropylazetidin-3- 260.2 1.3 yl)picolinamide 962 4-cyclopropyl-N-(1-(1-(2,5- 390.1 0.48 dichlorophenyl)ethyl)azetidin-3-yl)picolinamide 963 1-cyclopropyl-N-(1-(1-(4-((4- 475.3 0.97 (methylcarbamoyl)benzyl)oxy)phenyl)ethyl)azetidin- 3-yl)-1H-1,2,3-triazole-4-carboxamide 964 N-(1-(1-(2-chloro-3-(2- 416.2 10.5 hydroxyemoxy)phenyl)ethyl)azetidin-3-yl)-4- cyclopropylpicolinamide 965 N-(1-(1-(2-chloro-3-memoxyphenyl)ethyl)azetidin- 387.2 0.072\ 3-yl)-5-cyclopropylpyridazine-3-carboxamide 966 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 388.3 0.013 yl)-4-cyclopropylpicolinamide 967 N-(1-(4-(benzyloxy)benzyl)azetidin-3-yl)-4- 414.2 0.15 cyclopropylpicolinamide 968 1-cyclopropyl-N-(1-(1-(4-(2,2,2- 410.2 1.7 trifluoroethoxy)phenyl)ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 969 rac-N-(1-(((1r,3r)-3- 382.3 0.98 (benzyloxy)cyclobutyl)methyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 970 N-(1-(1-(5-chloro-2- 412.2 5.1 (difluoromethoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 971 1-cyclopropyl-N-(1-(1-(4-((4- 432.3 0.088 methylbenzyl)oxy)phenyl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 972 1-cyclopropyl-N-(1-(4-(pyridin-3- 405.3 1.3 ylmemoxy)benzyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 973 N-(1-(1-(2-chloro-3-(2,3- 436.2 >50 dihydroxypropoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 974 1-cyclopropyl-N-(1-(1-(4- 418.3 0.87 (phenoxymethyl)phenyl)ethyl)azetidin-3-yl)-1H- 1,2,3-triazole-4-carboxamide 975 N-(1-(1-(2-chloro-3-(2- 419.3 5.4 (methylamino)ethoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 976 N-(1-(1-(5-chloro-2- 414.2 1.8 (trifluoromethyl)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 977 N-(1-(1-(2-chloro-3-(2- 433.2 7.5 (dimethylamino)ethoxy)phenyl)ethyl)azetidin-3-yl)- 1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 978 N-(1-(1-(2-chloro-3-(2- 420.2 1.1 hydroxypropoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 979 1-cyclopropyl-N-(1-(1-methylpiperidin-2-yl)ethyl)- 278.2 >50 1H-1,2,3-triazole-4-carboxamide 980 N-(1-(2-(4-(benzyloxy)phenyl)propan-2-yl)azetidin- 432.3 0.99 3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 981 5-cyclopropyl-N-(1-(1-methylpiperidin-2- 289.2 >50 yl)ethyl)pyridazine-3-carboxamide 982 1-cyclopropyl-N-(1-((1-(3-methoxybenzyl)-1H- 408.3 0.169 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 983 1-cyclopropyl-N-(1-(4-(1-hydroxy-2- 418.2 1.39 phenylethyl)benzyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 984 rac-1-cyclopropyl-N-((R)-2,2-dimethyl-1-((R)-1- 340.2 18.9 phenylethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 985 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 412.2 0.0039 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 986 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 377.3 >50 yl)-5-cyclopropyl-1H-imidazole-2-carboxamide 987 N-(1-((1-(3-chlorobenzyl)-1H-pyrazol-4- 412.2 0.024 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 988 N-(1-(4-((1,3,4-thiadiazol-2- 412.2 1.9 yl)methoxy)benzyl)azetidin-3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 989 N-(1-(1-(5-chloro-2-(4- 456.2 >50.0 fluorophenoxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 990 1-cyclopropyl-N-(1-(1-(4-(piperidin-3- 425.2 3.3 ylmethoxy)phenyl)ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 991 1-cyclopropyl-N-(1-((1-(thiazol-2-ylmethyl)-1H- 385.2 0.76 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 992 1-cyclopropyl-N-(1-(4-(pyridin-2- 405.1 2.7 ylmethoxy)benzyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 993 1-cyclopropyl-N-(1-((1-(4-methylbenzyl)-1H- 392.3 0.016 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 994 1-cyclopropyl-N-(1-(1-(6-oxo-1,6-dihydropyridin-3- 329.2 5.4 yl)ethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 995 1-cyclopropyl-N-(1-((1-(2-methoxybenzyl)-1H- 408.2 1.3 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 996 N-(1-(1-(4-((4- 452.2 0.069 chlorobenzyl)oxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 997 N-(1-(1-(4-((3- 452.2 0.27 chlorobenzyl)oxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 998 1-cyclopropyl-N-(1-((1-isobutyl-1H-pyrazol-4- 343.4 2.4 yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 999 1-cyclopropyl-N-(1-(4-(thiazol-4- 411.2 1.1 ylmethoxy)benzyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 1000 1-cyclopropyl-N-(1-(piperidin-2-yl)ethyl)-1H-1,2,3- 264.1 >50 triazole-4-carboxamide 1001 N-(1-((1-(cyclobutylmethyl)-1H-pyrazol-4- 356.2 1.4 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3- triazole-4-carboxamide 1002 N-(1-(1-(2-chloro-4-methoxyphenyl)ethyl)azetidin- 376.2 0.088 3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide 1003 5-cyclopropyl-N-(1-(piperidin-2-yl)ethyl)pyridazine- 275.2 19.0 3-carboxamide 1004 1-cyclopropyl-N-(1-(1-(4-(2-oxo-2-(piperidin-1- 453.3 1.5 yl)ethoxy)phenyl)ethyl)azetidin-3-yl)-1H-1,2,3- triazole-4-carboxamide 1005 4-cyclopropyl-N-(1-(1-(2,3- 381.9 0.13 dimethoxyphenyl)ethyl)azetidin-3-yl)picolinamide 1006 1-cyclopropyl-N-(1-((1-(cyclopropylmethyl)-1H- 342.2 1.7 pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 1007 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 395.1 0.072 yl)-5-cyclopropyl-1,3,4-thiadiazole-2-carboxamide 1008 rac-N-(1-(((1s,3s)-3- 382.2 1.2 (benzyloxy)cyclobutyl)methyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 1009 N-(1-(1-(3-(2-aminoethoxy)-2- 405.3 5.7 chlorophenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H- 1,2,3-triazole-4-carboxamide 1012 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 411.1 yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H- imidazole-4-carboxamide 1017 1-cyclopropyl-N-(1-((1-((1-methyl-1H-pyrazol-4- 382.2 yl)methyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide 1020 N-(1-(1-(4-((4- 475.3 0.95 acetamidobenzyl)oxy)phenyl)ethyl)azetidin-3-yl)-1- cyclopropyl-1H-1,2,3-triazole-4-carboxamide 1021 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 379.2 0.065 yl)-5-cyclopropyl-1,3,4-oxadiazole-2-carboxamide 1022 N-(1-((1-benzyl-1H-pyrazol-4-yl)methyl)azetidin-3- 377.2 0.073 yl)-1-cyclopropyl-1H-imidazole-4-carboxamide 1023 5-cyclopropyl-N-((1R,3s,5S)-8-methyl-8- 287.2 6.3 azabicyclo[3.2.1]octan-3-yl)pyridazine-3- carboxamide 1024 5-cyclopropyl-N-((1R,3r,5S)-8-methyl-8- 287.2 >50 azabicyclo[3.2.1]octan-3-yl)pyridazine-3- carboxamide 1025 1-cyclopropyl-N-(1-(4-((1-methyl-1H-pyrazol-4- 408.3 1.2 yl)methoxy)benzyl)azetidin-3-yl)-1H-1,2,3-triazole- 4-carboxamide 1026 rac-1-cyclopropyl-N-((R)-2,2-dimethyl-1-((S)-1- 340.3 0.91 phenylethyl)azetidin-3-yl)-1H-1,2,3-triazole-4- carboxamide 1028 N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4- 413.2 yl)methyl)azetidin-3-yl)-5-cyclopropyl-1,3,4- oxadiazole-2-carboxamide *IC₅₀ values are an average of n = 1 to n = 50

In another embodiment, a Compound of the Disclosure is a compound having Formulae I-XVIII, provided that the compound is not N-(1-((4-acetamidophenyl)sulfonyl)piperidin-4-yl)benzamide:

In some embodiments, the disclosure relates to pharmaceutical compositions comprising N-(1-((4-acetamidophenyl)sulfonyl)piperidin-4-yl)benzamide and a pharmaceutically acceptable carrier.

In some embodiments, the disclosure relates to a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a subject, comprising administering to a subject in need thereof an effective amount of N-(1-((4-acetamidophenyl) sulfonyl)piperidin-4-yl)benzamide.

Definitions

For the purpose of the present disclosure, the terms used in connection with A or A¹ have the chemical structures set forth in Table 2, each of which may be optionally substituted with one or more substituents, e.g., 1, 2, 3, 4, or 5 substituents, depending on the nature of the group and the number of available positions. For example, when A or A¹ is 2-furanyl there are three carbon atoms for available for substitution. When A or A¹ is 2-naphthalenyl there are seven carbon atoms available for substitution. Substitution may occur at any available carbon or nitrogen atom. Optional substituents include, but are not limited to, halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, (carboxamido)alkyl, (cycloalkyl)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, or aralkyl.

TABLE 2 A or A¹ Chemical structure 1,2,3-triazolyl

1,2,4-triazolyl

1-imidazolyl

1-isoquinolinyl

1-pyrazolyl

2-(1,2,3,4-tetrahydroquinolinyl)

2-benzo[d]imidazolyl

2-benzo[d]thiazolyl

2-chromenyl-4-one

2-furanyl

2-imidazo[1,2-b]pyridazinyl

2-imidazolyl

2-indolyl

2-naphthalenyl

2-pyrazinyl

2-pyridyl

2-pyrimidinyl

2-pyrrolidinyl

2-pyrrolyl

2-quinolinyl

2-quinoxalinyl

2-thiazolo[5,4-c]pyridinyl

2-thiazolyl

2-thiophenyl

3-(1,2,3,4-tetrahydroisoquinoline)

3-(1,2,4-oxadiazolyl)

3-imidazo[1,2-a]pyrimidinyl

3-indazolyl

3-indolyl

3-isothiazolyl

3-pyrazolyl

3-pyridazinyl

3-pyridinyl-2-one

3-pyridyl

3-pyrrolo[3,2-b]pyridinyl

3-quinolinyl

4-(2,2-difluorobenzo[d][1,3]dioxolyl)

4-cyclohexanyl-1-amine

4-imidazolyl

4-indolinyl-2-one

4-indolyl

4-isothiazolyl

4-oxazolyl

4-piperidinyl

4-pyrazolyl

4-pyridyl

4-quinolinyl

5-(1,3-dihydro-2H-benzo[d]imidazolyl- 2-one)

5-(1,3-dihydro-2H-pyrrolo[2,3- b]pyridinyl-2-one)

5-(1,3-dihydro-2H-pyrrolo[2,3- c]pyridinyl-2-one)

5-(2,2-difluorobenzo[d][1,3]dioxolyl)

5-(2,4-dihydro-3H-1,2,4-triazolyl- 3-one)

5-4H-furo[3,2-b]pyrrolyl

5-benzo[c][1,2,5]oxadiazolyl

5-benzo[d][1,3]dioxolyl

5-benzo[d]oxazolyl-2(3H)-one

5-bicyclo[2.2.1]heptyl-2-ene

5-indolinyl-2,3-dione

5-indolinyl-2-one

5-indolyl

5-isoindolinyl-1-one

5-isoxazolyl

5-pyrazolo[3,4-c]pyridinyl

5-pyrazolyl

5-pyrimidinyl

5-thiazolyl

6-(1,2,3,4-tetrahydronaphthalenyl)

6-(3,4-dihydroquinolinyl-2(1H)-one)

6-(3,4-dihydroquinoxalinyl-2(1H)-one)

6-(4,5-dihydropyridazinyl-3(2H)-one)

6-benzo[b][1,4]oxazinyl-3-one

6-benzo[d]imidazolyl

6-benzo[d]oxazolyl-2(3H)-one

6-benzo[d]thiazolyl

6-chromenyl-2-one

6-imidazo[2,1-b]thiazole

6-indazolyl

6-indolinyl-2-one

6-indolyl

6-isoquinolinyl

6-quinolinyl

6-quinoxalinyl

6-quinoxalinyl-2(1H)-one

7-(3,4-dihydroquinolinyl-2(1H)-one)

7-(3,4-dihydroquinoxalin-2(1H)-one)

7-benzo[b][1,4]oxazinyl-3-one

7-indolinyl-2-one

7-quinolinyl

8-benzo[b][1,4]oxazinyl-3-one

cyclopropanyl

phenyl

4-(prop-1-en-1-yl)-imidazole

1-butanyl-imidazole

sec-butylcyclopropane

2-(ethylsulfonyl)propanyl

1-isobutylpyrrolidine

4-pyridyl 1-oxide

5-benzo[c][1,2,5]oxadiazolyl 1-oxide

For the purpose of the present disclosure, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atoms designated (i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is chosen from a straight chain C₁₋₁₀ alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C₃₋₁₀ alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C₁₋₆ alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C₃₋₆ alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C₁₋₄ alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C₃₋₄ alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C₃₋₄ alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C₁₋₁₀ alkyl groups include methyl (including —CD₃), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C₁₋₄ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionally substituted alkyl” as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl. In one embodiment, the alkyl is a C₁₋₆ alkyl. In another embodiment, the alkyl is a C₁₋₄ alkyl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include —CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, and —CH₂C₆H₁₁.

For the purpose of the present disclosure, the term “alkylenyl” as used herein by itself or part of another group refers to a divalent form of an alkyl group as defined above. In one embodiment, the alkylenyl is a divalent form of a C₁₋₆ alkyl. In one embodiment, the alkylenyl is a divalent form of a C₁₋₄ alkyl. Non-limiting exemplary alkylenyl groups include —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂C(CH₃)₂CH₂—.

For the purpose of the present disclosure, the term “cycloalkyl” as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group. In another embodiment, the cycloalkyl group is chosen from a C₃₋₆ cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.

For the purpose of the present disclosure, the term “optionally substituted cycloalkyl” as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is an (amino)cyclo alkyl. For the purpose of the present disclosure, the term “(amino)cycloalkyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is substituted with one amino or alkylamino group, and optionally one or two additional substituents. In one embodiment, the optionally substituted cycloalkyl is an (amino)cyclohexyl. For the purpose of the present disclosure, the term “(amino)cyclohexyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is a cyclohexyl group substituted with one amino or alkylamino group, and optionally one or two additional substituents. Non-limiting exemplary optionally substituted cycloalkyl groups include:

Non-limiting exemplary (amino)cycloalkyl groups include:

Non-Limiting Exemplary (Amino)Cyclohexyl Groups Include:

For the purpose of the present disclosure, the term “optionally substituted cyclohexyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is an optionally substituted cyclohexyl group.

For the purpose of the present disclosure, the term “cycloalkylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted cycloalkyl group as defined above. In one embodiment, the cycloalkylenyl is a “cyclohexylenyl.” The term “cyclohexylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted cyclohexyl group. Non-limiting exemplary cycloalkylenyl groups include:

For the purpose of the present disclosure, the term “1,4-cyclohexylenyl” as used herein by itself or part of another group refers to a cyclohexylenyl as defined above wherein the 1- and 4-positions of the cyclohexyl ring are substituted. Non-limiting exemplary 1,4-cyclohexylenyl groups include:

For the purpose of the present disclosure, the term “(cycloalkylenyl)alkyl” as used herein by itself or part of another group refers to an alkyl group substituted with a divalent form of an optionally substituted cycloalkyl group. In one embodiment, the cycloalkylenyl is a divalent for of optionally substituted cyclohexyl. In one embodiment, the alkyl is C₁₋₄ alkyl. Non-limiting exemplary (cycloalkylenyl)alkyl groups include:

For the purpose of the present disclosure, the term “cycloalkenyl” as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above. In one embodiment, the cycloalkenyl has one carbon-to-carbon double bond. In another embodiment, the cycloalkenyl group is chosen from a C₄₋₈ cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

For the purpose of the present disclosure, the term “optionally substituted cycloalkenyl” as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.

For the purpose of the present disclosure, the term “alkenyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. In another embodiment, the alkenyl group is chosen from a C₂₋₄ alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purpose of the present disclosure, the term “optionally substituted alkenyl” as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond. In one embodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. In another embodiment, the alkynyl group is chosen from a C₂₋₄ alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

For the purpose of the present disclosure, the term “optionally substituted alkynyl” as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

For the purpose of the present disclosure, the term “fluoroalkyl” as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine atoms. In another embodiment, the fluoroalkyl group is chosen from a C₁₋₄ fluoroalkyl group. Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.

For the purpose of the present disclosure, the term “hydroxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. In another embodiment, the hydroxyalkyl group is chosen from a C₁₋₄ hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

For the purpose of the present disclosure, the term “alkoxy” as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is chosen from a C₁₋₄ alkoxy group. In another embodiment, the alkoxy group is chosen from a C₁₋₄ alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, tert-butoxy, —OCH₂C≡CH, —OCH₂C≡CCH₃, and —OCH₂CH₂CH₂C≡CH.

For the purpose of the present disclosure, the term “alkylthio” as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. In one embodiment, the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limiting exemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, pentyloxymethyl, —CH₂OCH₂C≡CH and —CH₂OCH₂CH₂CH₂C≡CH.

For the purpose of the present disclosure, the term “haloalkoxy” as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “heteroalkyl” as used by itself or part of another group refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. In one embodiment, the heteroalkyl contains one oxygen and one nitrogen atom, e.g., a (hydroxyalkylamino)alkyl group, e.g., —CH₂N(CH₃)CH₂CH₂CH₂OH. In one embodiment, the heteroalkyl contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include —CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃, —CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, —NHCH₂CH₂N(H)CH₃, —NHCH₂CH₂OCH₃, —CH₂OCH₂CH₂NH₂, —CH₂OCH₂CH₂N(H)CH₂CH₃, and —OCH₂CH₂OCH₃.

For the purpose of the present disclosure, the term “aryl” as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C₆₋₁₄ aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is chosen from phenyl or naphthyl. In one embodiment, the aryl group is phenyl.

For the purpose of the present disclosure, the term “optionally substituted aryl” as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, (aralkyloxy)alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, heteroalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, (C₁₋₄ haloalkoxy)alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (carboxamido)alkyl-O—, mercapto alkyl, (heterocyclo)alkyl, (heterocyclo)alkyl-O—, (cycloalkylamino)alkyl, (hydroxyalkylamino)alkyl, (amino)(heteroaryl)alkyl, (heterocycloamino)alkyl (amino)(hydroxy)alkyl, (heteroaryl)alkyl, (hetero aryl)alkyl-O—, —N(R⁴³)(R⁴⁴), —CH₂N(R⁴³)(R⁴⁴), —CH₂N(H)C(═O)—R⁴⁵, and —N(H)C(═O)—R⁴⁵, wherein R⁴³ is hydrogen, C₁₋₄ alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R⁴⁴ is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, aralkyl, or (dialkylamino)alkyl; and R⁴⁵ is alkyl, alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or (heteroaryl)alkyl. In another embodiment, the optionally substituted aryl is substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, (aralkyloxy)alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, heteroalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, (C₁₋₄ haloalkoxy)alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercapto alkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (hydroxyalkylamino)alkyl, (amino)(heteroaryl)alkyl, (heterocycloamino)alkyl (amino)(hydroxy)alkyl, (heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), —CH₂N(H)C(═O)—R⁴⁵, and —N(H)C(═O)—R⁴⁵.

In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, or (amino)(hydroxy)alkyl substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl is meant to include aryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “arylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted aryl group as defined above. In one embodiment, the arylenyl is a divalent form of an optionally substituted phenyl. In one embodiment, the arylenyl is a divalent form of phenyl. Non-limiting exemplary alkylenyl groups include:

For the purpose of the present disclosure, the term “aryloxy” as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO—.

For the purpose of the present disclosure, the term “heteroaryloxy” as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.

For the purpose of the present disclosure, the term “aralkyloxy” or “arylalkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH₂O—.

For the purpose of the present disclosure, the term “(aralkyloxy)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an aralkyloxy group. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary “(aralkyloxy)alkyl” groups include —CH₂OCH₂(3-F-Ph) and —CH₂OCH₂CH₂CH₂(2-OMe-Ph).

For the purpose of the present disclosure, the term “heteroaryl” or “heteroaromatic” refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen, or sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In one embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl” is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide.

For the purpose of the present disclosure, the term “optionally substituted heteroaryl” as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), or —N(H)C(═O)—R⁴⁵, wherein R⁴³ is hydrogen or C₁₋₄ alkyl; R⁴⁴ is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R⁴⁵ is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, the optionally substituted heteroaryl has one substituent. In one embodiment, the substituent is amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, —N(R⁴³)(R⁴⁴), or —N(H)C(═O)—R⁴⁵. In another embodiment, the substituent is aralkyl or (heteroaryl)alkyl. Examples include:

In one embodiment, the optionally substituted is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted. The term optionally substituted heteroaryl is meant to include heteroaryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “heteroarylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group as defined above. In one embodiment, the heteroarylenyl is a divalent form of an optionally substituted pyridyl. Non-limiting exemplary heteroarylenyl groups include:

For the purpose of the present disclosure, the term “heterocycle” or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized. The term “heterocyclo” is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as β-lactam, γ-lactam, 6-lactam and 8-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term “heterocyclo” is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. In one embodiment, the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one

For the purpose of the present disclosure, the term “optionally substituted heterocyclo” as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle. In another embodiment, the optionally substituted heterocyclo is substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group. Non-limiting exemplary optionally substituted heterocyclo groups include:

For the purpose of the present disclosure, the term “heterocyclenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heterocyclo group as defined above. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted azetidine. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted piperidinyl. Non-limiting exemplary heterocyclenyl groups include:

For the purpose of the present disclosure, the term “optionally substituted pyrrolidinyl” as used by itself or as part of another group means that the optionally substituted heterocyclo as defined above is an optionally substituted pyrrolidinyl group.

For the purpose of the present disclosure, the term “optionally substituted pyrrolidinenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted pyrrolidinyl group as defined above. Non-limiting exemplary optionally substituted pyrrolidinenyl groups include:

For the purpose of the present disclosure, the term “amino” as used by itself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as used by itself or as part of another group refers to —NHR²², wherein R²² is C₁₋₆ alkyl. In one embodiment, R²² is C₁₋₄ alkyl. Non-limiting exemplary alkylamino groups include —N(H)CH₃ and —N(H)CH₂CH₃.

For the purpose of the present disclosure, the term “dialkylamino” as used by itself or as part of another group refers to —NR^(23a)R^(23b), wherein R^(23a) and R^(23b) are each independently C₁₋₆ alkyl. In one embodiment, R^(23a) and R^(23b) are each independently C₁₋₄ alkyl. Non-limiting exemplary dialkylamino groups include —N(CH₃)₂ and —N(CH₃)CH₂CH(CH₃)₂.

For the purpose of the present disclosure, the term “hydroxyalkylamino” as used by itself or as part of another group refers to —NR^(24a)R^(24b), wherein R^(24a) is hydrogen or C₁₋₄ alkyl, and R^(24b) is hydroxyalkyl. Non-limiting exemplary hydroxyalkylamino groups include —N(H)CH₂CH₂OH, —N(H)CH₂CH₂CH₂OH, —N(CH₃)CH₂CH₂OH, and —N(CH₃)CH₂CH₂CH₂OH.

For the purpose of the present disclosure, the term “(hydroxyalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an hydroxyalkylamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. A non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH₂N(CH₃)CH₂CH₂CH₂OH.

For the purpose of the present disclosure, the term “cycloalkylamino” as used by itself or as part of another group refers to —NR^(25a)R^(25b), wherein R^(25a) is optionally substituted cycloalkyl and R^(25b) is hydrogen or C₁₋₄ alkyl.

For the purpose of the present disclosure, the term “heterocycloamino” as used by itself or as part of another group refers to —NR^(25c)R^(25d), wherein R^(25c) is optionally substituted heterocyclo and R^(25d) is hydrogen or C₁₋₄ alkyl. Non-limiting exemplary heterocycloamino groups include:

For the purpose of the present disclosure, the term “(heterocycloamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an heterocycloamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl.

For the purpose of the present disclosure, the term “aralkylamino” as used by itself or as part of another group refers to —NR^(26a)R^(26b), wherein R^(26a) is aralkyl and R^(26b) is hydrogen or C₁₋₄ alkyl. Non-limiting exemplary aralkylamino groups include —N(H)CH₂Ph and —N(CH₃)CH₂Ph.

For the purpose of the present disclosure, the term “(amino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an amino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary (amino)alkyl groups include —CH₂NH₂, —C(NH₂)(H)CH₃, —CH₂CH₂NH₂, —CH₂C(NH₂)(H)CH₃, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, and —CH₂C(CH₃)₂CH₂NH₂

For the purpose of the present disclosure, the term “(alkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. A non-limiting exemplary (alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term “(dialkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary (dialkylamino)alkyl groups are —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term “(cycloalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary (cycloalkylamino)alkyl groups include —CH₂N(H)cyclopropyl, —CH₂N(H)cyclobutyl, and —CH₂N(H)cyclohexyl.

For the purpose of the present disclosure, the term “(aralkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an aralkylamino group. In one embodiment, the alkyl is a C₁₋₄ alkyl. A non-limiting exemplary (aralkylamino)alkyl group is —CH₂CH₂CH₂N(H)CH₂Ph.

For the purpose of the present disclosure, the term “(hydroxyalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an hydroxyalkylamino group. A non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH₂CH₂NHCH₂CH₂OH

For the purpose of the present disclosure, the term “(cyano)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., —CN, groups. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and —CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “(amino)(hydroxy)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, dialkylamino, or heterocyclo group and one hydroxy group. In one embodiment, the alkyl is a C₁₋₆ alkyl. In another embodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary (amino)(hydroxy)alkyl groups include:

For the purpose of the present disclosure, the term “(amino)(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino, and one carboxamido group. In one embodiment, the alkyl is a C₁₋₆ alkyl. Non-limiting exemplary (amino)(carboxamido)alkyl groups include:

For the purpose of the present disclosure, the term “(amino)(aryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group. In one embodiment, the alkyl is a C₁₋₆ alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (amino)(aryl)alkyl groups include:

For the purpose of the present disclosure, the term “(amino)(heteroaryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted heteroaryl group. In one embodiment, the alkyl is a C₁₋₆ alkyl. In one embodiment, the alkyl is a C₁₋₄ alkyl. In one embodiment, the optionally substituted heteroaryl group is an optionally substituted pyridyl. Non-limiting exemplary (amino)(heteroaryl)alkyl groups include:

For the purpose of the present disclosure, the term “(cycloalkyl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one optionally substituted cycloalkyl group. In one embodiment, the alkyl is a C₁₋₄ alkyl. In one embodiment, the cycloalkyl is a C₃₋₆ cycloalkyl. In one embodiment, the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group. Non-limiting exemplary (cycloalkyl)alkyl groups include:

For the purpose of the present disclosure, the term “(hydroxy)(aryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group. In one embodiment, the alkyl is a C₁₋₆ alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (hydroxy)(aryl)alkyl groups include:

For the purpose of the present disclosure, the term “carboxamido” as used by itself or as part of another group refers to a radical of formula —C(═O)NR^(26a)R^(26b), wherein R^(26a) and R^(26b) are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, aralkyl, (heteroaryl)alkyl, or optionally substituted heteroaryl, or R^(26a) and R^(26b) taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. In one embodiment, R^(26a) and R^(26b) are each independently hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and —CON(H)Ph.

For the purpose of the present disclosure, the term “(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include —CH₂CONH₂, —C(H)CH₃—CONH₂, and —CH₂CON(H)CH₃.

For the purpose of the present disclosure, the term “sulfonamido” as used by itself or as part of another group refers to a radical of the formula —SO₂NR^(27a)R^(27b), wherein R^(27a) and R^(27b) are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R^(27a) and R^(27b) taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO₂—, substituted by any of the above-mentioned optionally substituted alkyl groups. A non-limiting exemplary alkylsulfonyl group is —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO₂—, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is —SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a —SH group.

For the purpose of the present disclosure, the term “carboxy” as used by itself or as part of another group refers to a radical of the formula —COOH.

For the purpose of the present disclosure, the term “carboxyalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a —COOH. A non-limiting exemplary carboxyalkyl group is —CH₂CO₂H.

For the purpose of the present disclosure, the term “alkoxycarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkoxy group. Non-limiting exemplary alkoxycarbonyl groups are —CO₂Me and —CO₂Et.

For the purpose of the present disclosure, the term “aralkyl” or “arylalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the aralkyl group is a C₁₋₄ alkyl substituted with one optionally substituted aryl group. In another embodiment, the aralkyl group is a C₁ or C₂ alkyl substituted with one optionally substituted phenyl group. In another embodiment, the aralkyl group is a C₁ alkyl substituted with one optionally substituted phenyl group, i.e., a benzyl group wherein the phenyl is optionally substituted. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, —CHPh₂, —CH₂(4-OH-Ph), and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the term “ureido” as used by itself or as part of another group refers to a radical of the formula —NR^(30a)—C(═O)—NR^(30b)R^(30c), wherein R^(22a) is hydrogen, alkyl, or optionally substituted aryl, and R^(30b) and R^(30c) are each independently hydrogen, alkyl, or optionally substituted aryl, or R^(30b) and R^(30c) taken together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclo group. Non-limiting exemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as used by itself or as part of another group refers to a radical of the formula —NR^(28a)—C(═NR²⁹)—NR^(28b)R^(28c), wherein R^(28a), R^(28b), and R^(28c) are each independently hydrogen, alkyl, or optionally substituted aryl, and R²⁹ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂, and —NH—C(C═NH)—NHCH₃.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the (heterocyclo)alkyl is a C₁₋₄ alkyl substituted with one optionally substituted heterocyclo group. The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(heteroaryl)alkyl” or “heteroaralkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

For the purpose of the present disclosure, the term “alkylcarbonylamino” as used by itself or as part of another group refers to an alkylcarbonyl group attached to an amino. A non-limiting exemplary alkylcarbonylamino group is —NHCOCH₃.

The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H (or deuterium (D)), ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and ¹⁴C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number.” Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.

As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

The term “enantiomeric excess” or “ee” refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R−S|*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S=1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]_(obs)/[α]_(max))*100, where [α]_(obs) is the optical rotation of the mixture of enantiomers and [α]_(max) is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

The terms “enantiomerically pure” or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.

The terms “enantiomerically enriched” or “enantioenriched” refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.

The terms “a” and “an” refer to one or more.

The term “about,” as used herein, includes the recited number ±10%. Thus, “about 10” means 9 to 11.

The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparaginate, glutamate and the like. The term “pharmaceutically acceptable salt” as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).

Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.

The present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.

The present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.

The present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.

As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.

Within the meaning of the disclosure, “treatment” also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

The term “therapeutically effective amount” or “effective dose” as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.

The term “container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.

The term “insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the “label” for a pharmaceutical product.

The term “disease” or “condition” or “disorder” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. As demonstrated below, Compounds of the Disclosure inhibit SMYD proteins, such as SMYD3 and SMYD2 and can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.

In some embodiments, the Compounds of the Disclosure can be used to treat a “SMYD protein mediated disorder” (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder). A SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role. In some embodiments, a SMYD-mediated disorder is a proliferative disease.

In some embodiments inhibiting SMYD proteins, such as SMYD3 and SMYD2, is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2. In some embodiments, the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo. Exemplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition.

The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. The family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5. SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain. (See e.g., Abu-Farha et al. J Mol Cell Biol (2011) 3 (5) 301-308). The SMYD proteins have been found to be linked to various cancers (See e.g., Hamamoto et al. Nat Cell. Biol. 2004, 6: 731-740), Hu et al. Cancer Research 2009, 4067-4072, and Komatsu et al. Carcinogenesis 2009, 301139-1146.)

SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)).

Genetic knockdown of SMYD3 leads to a decrease in proliferation of a variety of cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)). Several studies employing RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012)). Moreover, SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models. The dependence of KRAS on SMYD3 was also shown to be dependent on its catalytic activity (Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)). SMYD3 function has also been implicated in colerectal cancers and RNAi mediated knockdown of SMYD3 has been shown to impair colerectal cell proliferation. (Peserico et al., Cell Physiol. 2015 Feb. 28. doi: 10.1002/jcp.24975. [Epub ahead of print]).

Furthermore, SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells. In a mouse model of respiratory syncytial virus (RSV) infection, a model in which iTreg cells have a critical role in regulating lung pathogenesis, SMYD3−/− mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb. 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]). In addition, as to development, Proserpio et al. have shown the importance of SMYD3 in the regulation of skeletal muscle atrophy (Proserpio et al. Genes Dev. 2013 Jun. 1; 27(11):1299-312), while Fujii et al. have elucidated the role of SMYD3 in cardiac and skeletal muscle development (Fujii et al. PLoS One. 2011; 6(8):e23491).

SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins. SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltransferase activity.

SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines. (See e.g., Komatsu et al., Carcinogenesis 2009, 30, 1139, and Cho et al., Neoplasia. 2012 June; 14(6):476-86). Moreover, high expression of SMYD2 has been shown to be a poor prognostic factor in both ESCC and pediatric ALL. (See e.g., Komatsu et al. Br J Cancer. 2015 Jan. 20; 112(2):357-64, and Sakamoto et al., Leuk Res. 2014 April; 38(4):496-502). Recently, Nguyen et al., have shown that a small molecule inhibitor of SMYD2 (LLY-507) inhibited the proliferation of several esophageal, liver and breast cancer cell lines in a dose-dependent manner. (Nguyen et al. J Biol Chem. 2015 Mar. 30. pii: jbc.M114.626861. [Epub ahead of print]).

SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb. 27; 290(9):5414-23).

In one aspect, the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2. Examples of treatable cancers include, but are not limited to, adrenal cancer, acidic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

In another embodiment, the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.

In another embodiment, the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).

In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.

In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

In another embodiment, the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.

Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present. Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995.

Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder. A useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

A pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such patients are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human.

A pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose. For example, administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation. The dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present disclosure can be administered orally. In another embodiment, a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation. In one embodiment, the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.

Alternatively, a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosure can be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosure can be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.

Alternatively, a pharmaceutical composition of the present disclosure can be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.

A pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution. Alternatively, a suspension of the active compound can be prepared as an oily suspension. Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400). An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. The suspension may optionally contain stabilizers.

In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.

General Synthesis of Compounds

Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In the General Schemes, A, Y, R^(12a), R^(12b), R^(13a), R^(13b), and Z of Formulae A-D are as defined in connection with Formula VI, unless otherwise indicated. In any of the General Schemes, suitable protecting can be employed in the synthesis, for example, when Z is (amino)alkyl or any other group that may group that may require protection. (See, Wuts, P. G. M.; Greene, T. W., “Greene's Protective Groups in Organic Synthesis”, 4th Ed., J. Wiley & Sons, N Y, 2007).

Compound A is converted to compound B (i.e, a compound having Formula VI, wherein X is —S(═O)₂—) by coupling with a suitable sulfonyl chloride (Z—SO₂Cl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.

Compound A is converted to compound C (i.e, a compound having Formula VI, wherein X is —C(═O)—) by coupling with a suitable acid chloride (Z—COCl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF, or by coupling with a suitable carboxylic acid (Z—CO₂H) in the presence of a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.

Compound A is converted to compound D (i.e, a compound having Formula VI, wherein X is —C(═O)C(R⁴)(H)—) by coupling with a suitable carboxylic acid (Z—C(H)R⁴CO₂H) in the presence of a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.

EXAMPLES General Synthetic Methods

General methods and experimental procedures for preparing and characterizing Compounds of the Disclosure are set forth in the general schemes above and the examples below. Wherever needed, reactions were heated using conventional hotplate apparatus or heating mantle or microwave irradiation equipment. Reactions were conducted with or without stirring, under atmospheric or elevated pressure in either open or closed vessels. Reaction progress was monitored using conventional techniques such as TLC, HPLC, UPLC, or LCMS using instrumentation and methods described below. Reactions were quenched and crude compounds isolated using conventional methods as described in the specific examples provided. Solvent removal was carried out with or without heating, under atmospheric or reduced pressure, using either a rotary or centrifugal evaporator.

Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates. Compound purity and mass confirmations were conducted using standard HPLC and/or UPLC and/or MS spectrometers and/or LCMS and/or GC equipment (i.e., including, but not limited to the following instrumentation: Waters Alliance 2695 with 2996 PDA detector connected with ZQ detector and ESI source; Shimadzu LDMS-2020; Waters Acquity H Class with PDA detector connected with SQ detector and ESI source; Agilent 1100 Series with PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEX API 2000 with ESI source; Agilent 7890 GC). Exemplified compounds were dissolved in either MeOH or MeCN to a concentration of approximately 1 mg/mL and analyzed by injection of 0.5-10 μL into an appropriate LCMS system using the methods provided in the following table. In each case the flow rate is 1 ml/min.

MS Heat MS Block Detector Mobile Temp Voltage Method Column Mobile Phase A Phase B Gradient Profile (° C.) (kV) A Shim-pack Water/ ACN/ 5% to 100% B in 250 1.5 XR-ODS 0.05% 0.05% 2.0 minutes, 100% 2.2 μm TFA TFA B for 1.1 minutes, 3.0 × 50 mm 100% to 5% B in 0.2 minutes, then stop B Gemini- Water/ ACN 5% to 100% B in 200 0.75 NX 3 μm 0.04% 2.0 minutes, 100% C18 Ammonia B for 1.1 minutes, 110A 100% to 5% B in 0.1 minutes, then stop C Shim-pack Water/ ACN/ 5% to 100% B in 250 0.85 XR-ODS 0.05% 0.05% 2.0 minutes, 100% 1.6 μm TFA TFA B for 1.1 minutes, 2.0 × 50 mm 100% to 5% B in 0.1 minutes, then stop D Shim-pack Water/ ACN/ 5% to 100% B in 250 0.95 XR-ODS 0.05% 0.05% 2.0 minutes, 100% 2.2 μm TFA TFA B for 1.1 minutes, 3.0 × 50 mm 100% to 5% B in 0.1 minutes, then stop

Compound structure confirmations were carried out using standard 300 or 400 MHz NMR spectrometers with nOe's conducted whenever necessary.

The following abbreviations are used herein:

Abbreviation Meaning ACN acetonitrile atm. atmosphere DCM dichloromethane DHP dihydropyran DIBAL diisobutyl aluminum hydride DIEA diisopropyl ethylamine DMF dimethyl formamide DMF-DMA dimethyl formamide dimethyl acetal DMSO dimethyl sulfoxide Dppf 1,1′- bis(diphenylphosphino)ferrocene EA ethyl acetate ESI electrospray ionization EtOH Ethanol FA formic acid GC gas chromatography H hour Hex hexanes HMDS hexamethyl disilazide HPLC high performance liquid chromatography IPA Isopropanol LCMS liquid chromatography/mass spectrometry MeOH Methanol Min Minutes NBS N-bromo succinimide NCS N-chloro succinimide NIS N-iodo succinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect Prep. Preparative PTSA para-toluene sulfonic acid Rf retardation factor rt room temperature RT retention time sat. Saturated SGC silica gel chromatography TBAF tetrabutyl ammonium fluoride TEA Triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography UPLC ultra performance liquid chromatography

Example 1 Synthesis of tert-butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate

Step 1: Synthesis of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (20.0 g, 87.23 mmol) in DCM (200 mL) was added HATU (36.46 g, 95.95 mmol), TEA (17.62 g, 174.46 mmol) and N,O-dimethylhydroxylamine (8.93 g, 91.59 mmol). The mixture was stirred at 25° C. for 16 h. The mixture was washed with H₂O and the DCM layer was evaporated and the residue purified by silica column (PE/EA=1:1) to give the tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (21.0 g, yield: 88.5%). ¹H NMR (400 MHz, CDCl₃): δ=4.27-4.01 (m, 2H), 3.71 (s, 3H), 3.19 (s, 3H), 2.85-2.70 (m, 3H), 1.75-1.62 (m, 4H), 1.46 (s, 9H).

Step 2: Synthesis of tert-butyl 4-acetylpiperidine-1-carboxylate

To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10.0 g, 36.76 mmol) in THF (150 mL) was added MeMgBr (24.5 mL, 73.52 mmol) at −78° C. The mixture was stirred at 25° C. for 16 h. TLC showed the reaction worked well. The mixture was quenched with aq. NH₄Cl and H₂O (100 mL) was added. The mixture was extracted with DCM (100 mL×3). The DCM layer was dried and evaporated to give the tert-butyl 4-acetylpiperidine-1-carboxylate (7.9 g, yield: 94.7%). ¹H NMR (400 MHz, CDCl₃): δ=4.10 (br. s., 2H), 2.88-2.70 (m, 2H), 2.46 (tt, J=3.6, 11.5 Hz, 1H), 2.17 (s, 3H), 1.84 (d, J=11.5 Hz, 2H), 1.58-1.48 (m, 2H), 1.48-1.41 (m, 9H).

Step 3: Synthesis of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (7.9 g, 34.8 mmol) in MeOH (100 mL) was added NH₄OAc (10.72 g, 139.2 mmol) and AcOH (1 mL). The mixture was stirred at 25° C. for 2 h, then was added NaBH₃CN (2.63 g, 41.76 mmol). The mixture was stirred at 25° C. for 16 h. The mixture was evaporated and 2N NaOH (50 mL) was added to the residue. The solution was extracted with DCM (100 mL×3). The DCM layer was washed with H₂O and brine dried and evaporated to give the tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (7.93 g, yield: 100%). ¹H NMR (400 MHz, CDCl₃): δ=4.15 (br. s., 2H), 2.77-2.57 (m, 3H), 1.76-1.59 (m, 2H), 1.46 (s, 9H), 1.33-10 (m, 5H), 1.06 (d, J=6.5 Hz, 3H).

Step 4: Synthesis of tert-butyl 4-(1-(((benzyloxy)carbonyl)amino)ethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (7.93 g, 34.8 mmol) in THF (80 mL) was added K₂CO₃ (9.6 g, 69.6 mmol) and Cbz-Cl (7.1 g, 41.76 mmol). The mixture was stirred at 25° C. for 16 h. The mixture diluted with H₂O and extracted with EA (50 mL×3) and the EA layer evaporated to give tert-butyl 4-(1-(((benzyloxy)carbonyl)amino)ethyl)piperidine-1-carboxylate (10.1 g, yield: 80.2%). ¹H NMR (400 MHz, DMSO-d₆): δ=7.42-7.23 (m, 5H), 7.16 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 3.94 (d, J=11.8 Hz, 2H), 3.45-3.34 (m, 1H), 2.71-2.55 (m, 2H), 1.67-1.42 (m, 3H), 1.38 (s, 9H), 1.13-0.89 (m, 5H).

Step 5: Synthesis of benzyl (1-(piperidin-4-yl)ethyl)carbamate

To a solution of tert-butyl 4-(1-(((benzyloxy)carbonyl)amino)ethyl)piperidine-1-carboxylate (10.1 g, 27.87 mmol) in EA (50 mL) was added HCl/EA (50 mL). The mixture was stirred at 25° C. for 16 h. Solvents were then evaporated to give the benzyl (1-(piperidin-4-yl)ethyl)carbamate as a white solid. (8.3 g, yield: 100%). ¹H NMR (400 MHz, DMSO-d₆): δ=8.88 (br. s., 1H), 8.50 (d, J=9.5 Hz, 1H), 7.42-7.30 (m, 5H), 7.26 (d, J=8.8 Hz, 1H), 5.04-4.98 (m, 2H), 3.46-3.41 (m, 1H), 3.24 (d, J=11.8 Hz, 2H), 2.84-2.71 (m, 2H), 1.74 (d, J=13.6 Hz, 2H), 1.53 (d, J=3.8 Hz, 1H), 1.40-1.28 (m, 2H), 1.05-0.99 (m, 3H).

Step 6: Synthesis of tert-butyl N-[(1S)-2-[4-[1-(benzyloxycarbonylamino)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate

To a solution of benzyl (1-(piperidin-4-yl)ethyl)carbamate (7.0 g, 23.43 mmol) in DCM (100 mL) was added HATU (8.9 g, 23.43 mmol), TEA (4.73 g, 46.86 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (4.43 g, 23.43 mmol). The mixture was stirred at 25° C. for 5 h. The mixture was washed with H₂O and the DCM layer evaporated. The residue was purified by silica column (PE/EA=1:1) to give the tert-butyl N-[(1S)-2-[4-[1-(benzyloxycarbonylamino)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (8.9 g, yield: 87.7%). ¹H NMR (400 MHz, CDCl₃): δ=7.37 (s, 5H), 5.58 (br. s., 1H), 5.15-5.03 (m, 2H), 4.60 (dd, J=7.4, 14.7 Hz, 3H), 3.96-3.86 (m, 1H), 3.68 (br. s., 1H), 2.99 (br. s., 1H), 2.54 (d, J=11.0 Hz, 1H), 1.91-1.63 (m, 3H), 1.44 (br. s., 9H), 1.28 (d, J=6.8 Hz, 4H), 1.21-1.07 (m, 4H).

Step 7: Synthesis of tert-butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate

To a solution of tert-butyl N-[(1S)-2-[4-[1-(benzyloxycarbonylamino)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (8.9 g, 20.55 mmol) in MeOH (100 mL) was added Pd/C (900 mg). The mixture was stirred at 25° C. for 16 hours under H₂ (50 psi). The reaction mixture was filtered and the filtrate was evaporated to give the tert-butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate. (5.6 g, yield: 91.2%). ¹H NMR (400 MHz, MeOD-d₄): δ=5.61 (t, J=7.2 Hz, 1H), 4.71-4.56 (m, 2H), 3.91 (br. s., 1H), 3.06-2.96 (m, 1H), 2.77-2.71 (m, 1H), 2.59-2.50 (m, 1H), 1.85-1.68 (m, 2H), 1.44 (d, J=3.0 Hz, 9H), 1.35-1.22 (m, 4H), 1.19-1.04 (m, 4H); LCMS (m/z): 300.2 [M+H]⁺.

Example 2 Synthesis of tert-butyl (3-(((1r,4r)-4-aminocyclohexyl)amino)-3-oxopropyl)carbamate

Step 1: Synthesis of tert-butyl N-[3-[[4-(benzyloxycarbonylamino)cyclohexyl]amino]-3-oxo-propyl]carbamate

To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (8.38 g, 44.30 mmol, 1.10 Eq) and TEA (8.2 g, 80 mmol, 2.0 Eq) in DCM (500 mL) was added HATU (15.31 g, 40.27 mmol, 1.00 Eq) in one portion at 20° C. The mixture was stirred at 20° C. for 30 minutes. Then benzyl N-(4-aminocyclohexyl)carbamate (10.00 g, 40.27 mmol, 1.00 Eq) was added in one portion at 20° C. The mixture was stirred at 20° C. for 12 hr at which point LCMS analysis showed the reaction was complete. The mixture was washed with water (400 mL×3) and extracted with DCM (600 mL×3). The combined organic layer was concentrated in vacuum. The residue was purified by recrystallization (from minimum MeOH) to afford tert-butyl N-[3-[[4-(benzyloxycarbonylamino)cyclohexyl]amino]-3-oxo-propyl]carbamate (14.60 g, 34.80 mmol, 86.42% yield) as white solid. 1H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J=7.78 Hz, 1H), 7.31-7.40 (m, 5H), 7.20 (d, J=7.78 Hz, 1H), 6.73 (t, J=5.40 Hz, 1H), 5.00 (s, 2H), 3.44 (d, J=6.78 Hz, 1H), 3.23 (dd, J=7.40, 3.14 Hz, 1H), 3.10 (q, J=6.61 Hz, 2H), 2.18 (t, J=7.40 Hz, 2H), 1.78 (br. s., 4H), 1.37 (s, 9H), 1.16-1.27 (m, 4H); LCMS (m/z): 320.2 [M+H−100]⁺.

Step 2: Synthesis of tert-butyl (3-(((1r,4r)-4-aminocyclohexyl)amino)-3-oxopropyl)carbamate

To a solution of tert-butyl N-[3-[[4-(benzyloxycarbonylamino)cyclohexyl]amino]-3-oxo-propyl]carbamate (14.60 g, 34.80 mmol, 1.00 Eq) in MeOH (500 mL) was added Pd/C (5 g) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50 psi) at 50° C. for 12 hours. LCMS showed the starting material was consumed completely. The reaction mixture was filtered and concentrated to give tert-butyl N-[3-[(4-aminocyclohexyl) amino]-3-oxo-propyl]carbamate (9.80 g, 34.34 mmol, 98.67% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J=7.53 Hz, 1H), 6.63-6.84 (m, 1H), 3.43 (br. s., 1H), 3.09 (q, J=6.78 Hz, 2H), 2.60 (br. s., 1H), 2.18 (t, J=7.28 Hz, 2H), 1.70-1.82 (m, 4H), 1.37 (s, 9H), 1.08-1.20 (m, 4H); LCMS (m/z): 230.2 [M+H−56]⁺.

Example 3 Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-6-chloro-2-oxoindoline-5-carboxamide (Cpd. No. 490)

Step 1: Synthesis of ((2S)-1-(4-(1-(6-chloro-2-oxoindoline-5-carboxamido) ethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate

To a mixture of 6-chloro-2-oxoindoline-5-carboxylic acid (100.00 mg, 472.59 umol, 1.00 Eq), HATU (179.69 mg, 472.59 umol, 1.00 Eq) and TEA (47.82 mg, 472.59 umol, 1.00 Eq) in DCM (10 mL) was added tert-butyl ((2S)-1-(4-(1-amino ethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (141.50 mg, 472.59 umol, 1.00 Eq). The mixture was stirred at 20° C. for 3 hours. LCMS showed the reaction was complete. Water (5 mL) was added to the reaction and the aqueous phase was extracted with DCM (10 mL×3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford tert-butyl ((2S)-1-(4-(1-(6-chloro-2-oxoindoline-5-carboxamido)ethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (100.00 mg, crude). LCMS (m/z): 493.2 [M+H]⁺.

Step 2: Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-6-chloro-2-oxoindoline-5-carboxamide

To a solution of tert-butyl ((2S)-1-(4-(1-(6-chloro-2-oxoindoline-5-carboxamido)ethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (100.00 mg, 202.84 umol, 1.00 Eq) in DCM (10 mL) was added dropwise TFA (3 mL) at 0° C. The resulting solution was then stirred for 3 hours at 25° C. TLC showed the reaction was complete. The mixture was evaporated and purified by prep-HPLC to afford N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-6-chloro-2-oxoindoline-5-carboxamide (38.50 mg, yield: 48.31%). ¹H NMR (400 MHz, MeOD-d₄): =7.29 (s, 1H), 6.95 (s, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.45-4.38 (m, 1H), 3.91 (d, J=12.3 Hz, 2H), 3.54 (s, 2H), 3.15 (br. s., 2H), 2.72-2.63 (m, 1H), 2.01-1.85 (m, 2H), 1.75 (br. s., 1H), 1.46 (dd, J=6.9, 11.7 Hz, 3H), 1.29-1.18 (m, 4H). LCMS (m/z): 393.2 [M+H]⁺.

Example 4 Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxoindoline-5-carboxamide Hydrochloride (Cpd. No. 86)

Step 1: Synthesis of tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxoindoline-5-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate

To a stirred solution of 2-oxoindoline-5-carboxylic acid (0.177 g, 1.00 mmol) in DMF (2 mL), were added EDCI.HCl (0.24 g, 1.25 mmol), HOBt (0.168 g, 1.25 mmol) and triethylamine (0.35 mL, 2.5 mmol). The solution was stirred for 10 min at 0° C. tert-Butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.25 g, 0.83 mmol) was added and the reaction stirred at rt for 6 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxoindoline-5-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.11 g, 28%). LCMS: 359.25 (M-Boc)⁺.

Step 2: Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxoindoline-5-carboxamide Hydrochloride

To a stirred solution of tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxoindoline-5-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.1 g, 0.47 mmol) in dioxane (2 mL) was added 4 M dioxane:HCl solution (4 mL) at 0° C. and the reaction mixture stirred at rt for 5 h. The progress of the reaction was monitored by TLC. After complete consumption of tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxoindoline-5-carboxamido)ethyl) piperidin-1-yl)propan-2-yl)carbamate, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxoindoline-5-carboxamide hydrochloride (0.08 g, 93%). ¹H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.06 (q, J=11.0, 8.4 Hz, 4H), 7.77-7.70 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 4.38-4.35 (m, 2H), 3.85 (d, J=13.9 Hz, 2H), 3.53 (s, 2H), 3.09-2.90 (m, 1H), 2.57 (dd, J=25.3, 12.8 Hz, 1H), 1.75 (dd, J=26.2, 12.6 Hz, 3H), 1.3-1.28 (m, 3H), 1.12 (d, J=6.8 Hz, 4H), 1.02 (d, J=12.5 Hz, 1H); LCMS: 359.25 (M+1)⁺.

Example 5 Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide Hydrochloride (Cpd. No. 94)

Step 1: Synthesis of tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate

To a stirred solution of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (0.2 g, 0.66 mmol) in DMF (1.5 mL) was added EDCI.HCl (0.191 g, 1.00 mmol), HOBt (0.091 g, 0.66 mmol) and diisopropylethylamine (0.34 mL, 2.00 mmol). The solution was stirred for 10 min at 0° C. After that, tert-butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.142 g, 0.80 mmol) was added and the reaction stirred at rt for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.104 g, 33%). LCMS: 361.05 (M-Boc)⁺.

Step 2: Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide Hydrochloride

To a stirred solution of ((2S)-1-oxo-1-(4-(1-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.03 g, 0.08 mmol) in dioxane (1 mL) at 0° C. was added 4M dioxane:HCl solution (1 mL). The reaction mixture was stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and hexane to obtain N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide hydrochloride (0.008 g, 36%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 8.72 (d, J=12.3 Hz, 1H), 8.42 (q, J=8.1, 7.1 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.1 Hz, 1H), 3.54 (s, 2H), 3.25 (d, J=12.4 Hz, 2H), 3.16 (t, J=6.1 Hz, 2H), 2.82 (q, J=11.8 Hz, 2H), 2.62 (s, 1H), 1.79 (d, J=13.4 Hz, 2H), 1.35-1.32 (m, 2H); LCMS: 274.15 (M+H)⁺

Example 6 Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (Cpd. No. 93)

Step 1: Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide Hydrochloride

To a stirred solution of 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (0.2 g, 0.66 mmol) in DMF (1.5 mL) was added EDCI.HCl (0.191 g, 1.00 mmol), HOBt (0.091 g, 0.66 mmol) and diisopropylethylamine (0.34 mL, 2.00 mmol). The solution was stirred for 10 min at 0° C. After that tert-butyl ((2S)-1-(4-(1-aminoethyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.142 g, 0.80 mmol) was added and the reaction stirred at rt for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.140 g, 45%). LCMS: 360.2 (M-Boc)⁺.

Step 2: Synthesis of N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide Hydrochloride

To a stirred solution of tert-butyl ((2S)-1-oxo-1-(4-(1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamido)ethyl)piperidin-1-yl)propan-2-yl)carbamate (0.1 g, 0.21 mmol) in dioxane (2 mL) at 0° C. was added 4M dioxane:HCl solution (1 mL). The reaction mixture was stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and hexane to obtain N-(1-(1-((S)-2-aminopropanoyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide hydrochloride (0.060 g, 69%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (d, J=16.4 Hz, 2H), 8.10 (p, J=8.9, 7.6 Hz, 4H), 7.55-7.52 (m, 1H), 7.44 (q, J=2.0 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.44-4.24 (m, 2H), 3.88-3.86 (m, 2H), 3.09-2.91 (m, 1H), 2.6-2.57 (m, 1H), 1.83-1.64 (m, 3H), 1.33-0.99 (m, 8H); LCMS: 360.25 (M+1)⁺.

Example 7 N-(1-(4-aminobutanoyl)piperidin-4-yl)-1H-1,2,4-triazole-5-carboxamide (Cpd. No. 560)

Step 1: Synthesis of tert-butyl 4-(1H-1,2,4-triazole-5-carbonylamino)piperidine-1-carboxylate

To a solution of 1H-1,2,4-triazole-5-carboxylic acid (2.00 g, 17.69 mmol, 1.00 Eq) in DMF (100 mL) was added TEA (2.68 g, 26.53 mmol, 1.50 Eq), BOP—Cl (4.95 g, 19.46 mmol, 1.10 Eq), and tert-butyl 4-aminopiperidine-1-carboxylate (3.90 g, 19.46 mmol, 1.10 Eq). The reaction mixture was stirred at 20° C. for 12 hr. The reaction mixture was concentrated and dissolved in MeOH, filtered, the organic layer was concentrated and purified by silica gel column chromatography to give tert-butyl 4-(1H-1,2,4-triazole-5-carbonylamino)piperidine-1-carboxylate (3.13 g, 10.60 mmol, 59.9% yield) as a yellow solid. LCMS (m/z): 240.1 [M+H−56]⁺.

Step 2: Synthesis of N-(4-piperidyl)-1H-1,2,4-triazole-5-carboxamide

To a solution of tert-butyl 4-(1H-1,2,4-triazole-5-carbonylamino)piperidine-1-carboxylate (3.13 g, 10.60 mmol, 1.00 Eq) in DCM (50 mL) was added TFA (10 mL). The reaction mixture was stirred at 20° C. for 5 hr. The reaction mixture was concentrated and lyophilized to afford N-(4-piperidyl)-1H-1,2,4-triazole-5-carboxamide (6.00 g, 19.40 mmol, 91.51% yield) as a light yellow solid. LCMS (m/z): 196.2 [M+H]⁺

Step 3: Synthesis of tert-butyl (4-(4-(1H-1,2,4-triazole-5-carboxamido)piperidin-1-yl)-4-oxobutyl)carbamate

To a mixture of 4-((tert-butoxycarbonyl)amino)butanoic acid (203.00 mg, 998.87 umol, 1.00 q) and HATU (379.80 mg, 998.87 umol, 1.00 Eq) in DCM (10 mL) was added Et₃N (202.15 mg, 2.00 mmol, 2.00 Eq) in one portion at 20° C. The mixture was stirred at 20° C. for 30 min. Then N-(piperidin-4-yl)-1H-1,2,4-triazole-5-carboxamide (195.00 mg, 998.87 umol, 1.00 Eq) was added in one portion at 20° C. The mixture was stirred at 20° C. for 12 h. LCMS showed the reaction was complete. The reaction mixture was washed with water (40 mL×3) and extracted with DCM (50 mL×3). The combined organic layer was concentrated under vacuum. The residue was purified by prep-HPLC to afford tert-butyl (4-(4-(1H-1,2,4-triazole-5-carboxamido)piperidin-1-yl)-4-oxobutyl)carbamate (200.00 mg, 525.71 umol, 52.63% yield) as white solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.45 (s, 1H) 4.54 (d, J=13.30 Hz, 1H) 4.13-4.21 (m, 1H) 4.01 (d, J=13.80 Hz, 1H) 3.23-3.30 (m, 1H) 3.11 (t, J=6.78 Hz, 2H) 2.85 (t, J=11.67 Hz, 1H) 2.46 (t, J=7.53 Hz, 2H) 1.97-2.07 (m, 2H) 1.78 (quip, J=7.15 Hz, 2H) 1.53-1.65 (m, 2H) 1.38-1.53 (m, 9H); LCMS (m/z): 381.2 [M+H]⁺.

Step 4: Synthesis of N-(1-(4-aminobutanoyl)piperidin-4-yl)-1H-1,2,4-triazole-5-carboxamide

To a mixture of tert-butyl (4-(4-(1H-1,2,4-triazole-5-carboxamido)piperidin-1-yl)-4-oxobutyl)carbamate (200.00 mg, 525.71 umol, 1.00 Eq) in DCM (20 mL) was added TFA (5 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min. The reaction then warmed slowly to 20° C. and stirred at this temperature for another 12 h. LCMS showed the reaction complete. The mixture was concentrated under reduced pressure at ° C. The residue was purified by prep-HPLC to afford N-(1-(4-aminobutanoyl)piperidin-4-yl)-1H-1,2,4-triazole-5-carboxamide (104.20 mg, 50.26% yield) as colorless oil (TFA salt). ¹H NMR (400 MHz, MeOD-d4) δ 8.49 (s, 1H) 4.54 (d, J=13.55 Hz, 1H) 4.12-4.21 (m, 1H) 4.00 (d, J=13.80 Hz, 1H) 3.25 (t, J=11.80 Hz, 1H) 3.02 (t, J=7.28 Hz, 2H) 2.86 (t, J=11.67 Hz, 1H) 2.60 (t, J=6.90 Hz, 2H) 1.92-2.08 (m, 4H) 1.46-1.73 (m, 2H); LCMS (m/z): 281.1 [M+H]⁺

Example 8 Synthesis of N-((1r,4r)-4-aminocyclohexyl)-1-benzyl-3-methyl-1H-pyrazole-5-carboxamide Hydrochloride (Cpd. No. 29)

Step 1: Synthesis of tert-butyl ((1r,4r)-4-(1-benzyl-3-methyl-1H-pyrazole-5-carboxamido)cyclohexyl)carbamate

To a stirred solution of 1-benzyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.150 g, 0.69 mmol) in DMF (5 mL) was added HATU (0.393 g, 1.0 mmol) and diisopropylethylamine (0.24 mL, 1.4 mmol). The solution was stirred for 10 min at 0° C. tert-Butyl ((1r,4r)-4-aminocyclohexyl)carbamate (0.147 g, 0.69 mmol) was added and the reaction stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((1r,4r)-4-(1-benzyl-3-methyl-1H-pyrazole-5-carboxamido)cyclohexyl)carbamate (0.08 g, 25%). LCMS: 313.1 (M−100)⁺.

Step 2: Synthesis of N-((1r,4r)-4-aminocyclohexyl)-1-benzyl-3-methyl-1H-pyrazole-5-carboxamide Hydrochloride

To a stirred solution of tert-butyl ((1r,4r)-4-(1-benzyl-3-methyl-1H-pyrazole-5-carboxamido)cyclohexyl)carbamate (0.05 g, 0.121 mmol) in dioxane (1 mL) at 0° C. was added 4 M dioxane:HCl (1.5 mL). The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the solvent was removed under reduced pressure to obtain a crude residue. The material was purified by repeated washing with ether and pentane to obtain N-((1r,4r)-4-aminocyclohexyl)-1-benzyl-3-methyl-1H-pyrazole-5-carboxamide hydrochloride (0.03 g, 51%). ¹H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J=7.8 Hz, 1H), 7.94 (d, J=5.3 Hz, 3H), 7.33-7.10 (m, 5H), 6.66 (s, 1H), 5.60 (s, 2H), 2.96 (d, J=10.9 Hz, 1H), 2.16 (s, 3H), 1.96 (d, J=10.4 Hz, 2H), 1.83 (d, J=11.1 Hz, 2H), 1.47-1.26 (m, 4H); LCMS: 313.2 (M+H)⁺.

Example 9 Synthesis of N-((1r,4r)-4-aminocyclohexyl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide Hydrochloride

Step 1: Synthesis of tert-butyl ((1r,4r)-4-(1-cyclopropyl-1H-1,2,3-triazole-4-carboxamido)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (0.090 g, 0.420 mmol) in DMF (2 mL) was added EDCI (0.096 g, 0.504 mmol), HOBT (0.068 g, 0.504 mmol) and DIPEA (0.3 mL) and the solution stirred for 10 min at 0° C. 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (0.064 g, 0.420 mmol) was then added and the reaction mixture stirred at rt for 2 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na₂SO₄ and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to afford tert-butyl ((1r,4r)-4-(1-cyclopropyl-1H-1,2,3-triazole-4-carboxamido)cyclohexyl)carbamate (0.035 g, 24%). LCMS: 250.1 (M−100)⁺ observed.

Step 2: Synthesis of N-((1r,4r)-4-aminocyclohexyl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide Hydrochloride

To a stirred solution of tert-butyl ((1r,4r)-4-(1-cyclopropyl-1H-1,2,3-triazole-4-carboxamido)cyclohexyl)carbamate (0.035 g, 0.10 mmol) in methanol (3 mL) was added 4M methanol:HCl (3 mL) at 0° C. and the reaction stirred at rt for 16 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was purified by washings with diethyl ether and DCM to obtain N-((1r,4r)-4-aminocyclohexyl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide hydrochloride (0.013 g, 49%). ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.97 (s, 2H), 4.1-4.05 (m, J=7.5, 3.9 Hz, 1H), 3.75-3.66 (m, 1H), 3.01-2.88 (m, 1H), 1.97 (d, J=10.5 Hz, 2H), 1.83 (d, J=9.5 Hz, 2H), 1.55-1.34 (m, 4H), 1.25-1.07 (m, 4H); LCMS: 250.05 (M+H)⁺.

Example 10 Synthesis of 2-oxo-N-(piperidin-4-ylmethyl)indoline-5-carboxamide Hydrochloride (Cpd. No. 100)

Step 1: Synthesis of tert-butyl 4-((2-oxoindoline-5-carboxamido)methyl) piperidine-1-carboxylate

To a stirred solution of 2-oxoindoline-5-carboxylic acid (0.7 g, 3.95 mmol) in DMF (5 mL) was added EDCI.HCl (1.13 g, 5.92 mmol), HOBt (0.8 g, 5.92 mmol) and triethylamine (1.7 mL, 11.8 mmol). The solution was stirred for 10 min at 0° C. After that tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.93 g, 4.34 mmol) was added and the reaction stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue which was purified by preparative HPLC to afford tert-butyl 4-((2-oxoindoline-5-carboxamido)methyl)piperidine-1-carboxylate (0.130 g, 8%) LCMS: 274.1 (M-Boc)⁺.

Step 2: Synthesis of 2-oxo-N-(piperidin-4-ylmethyl)indoline-5-carboxamide Hydrochloride

To a stirred solution of tert-butyl 4-((2-oxoindoline-5-carboxamido)methyl)piperidine-1-carboxylate (0.03 g, 0.08 mmol) in dioxane (1 mL) at 0° C. was added 4M dioxane:HCl solution (1 mL). The reaction mixture was stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and hexane to obtain 2-oxo-N-(piperidin-4-ylmethyl)indoline-5-carboxamide hydrochloride (0.008 g, 36%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 8.72 (d, J=12.3 Hz, 1H), 8.42 (q, J=8.1, 7.1 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.1 Hz, 1H), 3.54 (s, 2H), 3.25 (d, J=12.4 Hz, 2H), 3.16 (t, J=6.1 Hz, 2H), 2.82 (q, J=11.8 Hz, 2H), 2.62 (s, 1H), 1.79 (d, J=13.4 Hz, 2H), 1.35-1.32 (m, 2H); LCMS: 274.15 (M+H)⁺.

Example 11 Synthesis of 2-oxo-N-((1R,3r,5SR)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,3-dihydrobenzo[d]oxazole-6-carboxamide Hydrochloride (Cpd. No. 601)

Step 1: Synthesis of benzyl4-(((1R,3r,5S)-3-(2,2,2-trichloroethoxy)carbonylamino)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 100-mL round-bottom flask was placed 2,2,2-trichloroethyl N-[(1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (780 mg, 2.59 mmol, 1.00 equiv), dichloromethane (10 mL), TEA (0.93 g) added dropwise at 0° C. Then benzyl 4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (1 g, 3.01 mmol, 1.17 equiv) was added in several portions. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was chromatographed on a silica gel column with dichloromethane/methanol (20:1-10:1). This resulted in 1.3 g (84%) of benzyl 4-[[(1R,3r,5S)-3-[[(2,2,2-trichloro ethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.32 (m, 5H), 5.32-5.10 (m, 2H), 4.48 (s, 2H), 4.27-4.12 (m, 4H), 4.00-3.96 (m, 1H), 2.93-2.80 (m, 4H), 2.30-2.07 (m, 5H), 1.98-1.91 (m, 6H), 1.30-1.26 (m, 3H) ppm. LCMS (method A, ESI): RT=1.32 min, m/z=620.2 [M+Na]⁺.

Step 2: Synthesis of benzyl 4-(((1R,3r,5S)-3-amino-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 100-mL round-bottom flask was placed benzyl 4-[[(1R,3r,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (1 g, 1.68 mmol, 1.00 equiv), acetic acid (15 mL), water (1 mL), and zinc (1.63 g, 24.92 mmol, 14.88 equiv). The resulting mixture was stirred for 2 h at room temperature and then diluted with 30 mL of H₂O. The solids were filtered out. The pH value of the filtrate was adjusted to 9 with NaOH (40%, aq.). The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.7 g (99%) of benzyl 4-[[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as a white solid. LCMS (method D, ESI): RT=0.85 min, m/z=422.3 [M+H]⁺.

Step 3: Synthesis of benzyl 4-(((1R,3r,5S)-3-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 25-mL round-bottom flask was placed 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carboxylic acid (100 mg, 0.56 mmol, 2.35 equiv), N,N-dimethylformamide (10 mL), HOBT (135 mg, 2.00 equiv) and EDCI (191 mg, 2.00 equiv). Then benzyl 4-[[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (100 mg, 0.24 mmol, 1.00 equiv) was added in several portions. After complete addition, TEA (250 mg, 5.00 equiv) was added dropwise. The resulting solution was stirred for 1 h at room temperature. The mixture was concentrated under vacuum and the residue diluted with 10 mL of H₂O. This mixture was extracted with 3×10 ml, of ethyl acetate and the organic layers combined. The combined extracts were washed with 2×30 mL of brine, dried, and concentrated. The residue was chromatographed on a silica gel column with dichloromethane/methanol (10/1). This resulted in 100 mg (72%) of benzyl 4-[[(1R,3r,5S)-3-(2-oxo-2,3-dihydro-1,3-benzoxazole-6-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as yellow oil. LCMS (method D, ESI): RT=1.38 min, m/z=583.0 [M+H]⁺.

Step 4: Synthesis of 2-oxo-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,3-dihydrobenzo[d]oxazole-6-carboxamide

Into a 25-mL round-bottom flask was placed benzyl 4-[[(1R,3r,5S)-3-(2-oxo-2,3-dihydro-1,3-benzoxazole-6-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (100 mg, 0.17 mmol, 1.00 equiv) and hydrochloric acid (12N, 10 mL). The resulting solution was stirred for 4 h at room temperature and then concentrated under vacuum. The residue was applied onto Pre-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm. The product was dissolved again into hydrochloric acid (5 mL, 12 N) and concentrated under vacuum. This resulted in 7.3 mg (9%) of 2-oxo-N-[(1R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2,3-dihydro-1,3-benzoxazole-6-carboxamide as a white solid. ¹H NMR (300 MHz, D₂O) δ: 7.52-7.49 (m, 2H), 7.18-7.16 (m, 1H), 4.21 (s, 2H), 4.08-4.03 (m, 1H), 3.38-3.34 (m, 2H), 3.20-3.18 (m, 2H), 3.02-2.93 (m, 2H), 2.24-1.94 (m, 11H), 1.54-1.51 (m, 2H) ppm. LCMS (method D, ESI): RT=1.65 min, m/z=449.2 [M−HCl+H]⁺.

Example 12 Synthesis of (2R)-2-methyl-3-oxo-N-[(1R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide Hydrochloride (Cpd. No. 625)

Step 1: Synthesis of methyl 3-(2-bromopropanamido)-4-hydroxybenzoate

Into a 100-mL round-bottom flask was placed ethyl acetate (10 mL), water (10 mL), methyl 3-amino-4-hydroxybenzoate (1 g, 5.98 mmol, 1.00 equiv), and sodium bicarbonate (553 mg, 1.10 equiv). This was followed by the addition 2-bromopropanoyl bromide (1.3 g, 6.02 mmol, 1.00 equiv) which was added dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature. The mixture was then washed with 2×30 mL of H₂O and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 1.5 g (83%) of methyl 3-(2-bromopropanamido)-4-hydroxybenzoate as a brown solid. ¹H NMR (300 MHz, CDCl₃) δ: 8.89 (s, 1H), 8.43 (s, 1H), 7.89-7.82 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 4.65 (q, J=14.1 Hz, 1H), 3.07 (s, 3H), 2.01 (d, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.30 min, m/z=302.0 [M+H]⁺.

Step 2: Synthesis of methyl 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 100-mL round-bottom flask was placed N,N-dimethylformamide (10 mL), methyl 3-(2-bromopropanamido)-4-hydroxybenzoate (1.5 g, 4.96 mmol, 1.00 equiv), and potassium carbonate (880 mg, 1.30 equiv). The resulting mixture was stirred for 15 h at room temperature. The mixture was then diluted with 30 mL of H₂O. The solids were collected by filtration. This resulted in 1 g (91%) of methyl 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ : 8.29 (s, 1H), 7.72 (q, J=8.4 Hz, 1H), 7.56 (d, J=2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.77 (q, J=14 Hz, 1H), 3.93 (s, 3H), 1.64 (d, J=7.2 Hz, 3H) ppm. LCMS (method C, ESI): RT=0.96 min, m/z=222.0 [M+H]⁺.

Step 3: Synthesis of 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b]1,4]oxazine-6-carboxylic Acid

Into a 100-mL round-bottom flask was placed tetrahydrofuran (15 mL), methanol (15 mL), water (10 mL), and methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxylate (1 g, 4.52 mmol, 1.00 equiv). This was followed by the addition of a solution of sodium hydroxide (362 mg, 2.00 equiv) in 5 ml H₂O which was added dropwise with stirring at 0° C. The resulting solution was stirred for 10 min at 0° C. in an ice/salt bath. The resulting solution was allowed to react, with stirring, for an additional 15 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was diluted with 30 mL of H₂O and the pH adjusted to 3-4 with hydrochloric acid (1 N). The solids were collected by filtration. This resulted in 900 mg (96%) of 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid as a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 7.68 (q, J=8.4 Hz, 1H), 7.59 (d, J=2 Hz, 1H), 4.47 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.75 (q, J=13.6 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H) ppm. LCMS (method A, ESI): RT=1.08 min, m/z=208.0 [M+H]⁺.

Step 4: Synthesis of tert-butyl (1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 100-mL round-bottom flask was placed N,N-dimethylformamide (50 mL), 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (500 mg, 2.41 mmol, 1.00 equiv), EDCI (923 mg, 2.00 equiv), HOBT (652 mg, 2.00 equiv), and tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (710 mg, 3.14 mmol, 1.30 equiv). This was followed by the addition of TEA (1232 mg, 5.0 equiv) which was added dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at room temperature. The reaction mixture was then diluted with 50 mL of EA. The resulting mixture was washed with 3×30 mL of H₂O and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (4:1). This resulted in 800 mg (80%) of tert-butyl (1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.66 (s, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.22 (q, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.51 (d, J=6.8 Hz, 1H), 4.72 (q, J=13.6 Hz, 1H), 4.39-4.20 (m, 3H), 2.45-2.25 (m, 2H), 2.20-2.10 (m, 2H), 1.95-1.75 (m, 4H), 1.60 (d, J=7.2 Hz, 3H), 1.50 (s, 9H) ppm. LCMS (method C, ESI): RT=1.08 min, m/z=416.0 [M+H]⁺.

Step 5: Synthesis of N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 100-mL round-bottom flask was placed dichloromethane (20 mL) and tert-butyl (1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.93 mmol, 1.00 equiv). To the above, hydrogen chloride (gas) was introduced. The resulting solution was stirred for 4 h at room temperature and then was concentrated under vacuum. The residue was diluted with 40 mL of H₂O. The pH was adjusted to 8 with saturated aqueous sodium carbonate and the resulting mixture extracted with 3×40 mL of DCM. The organic layers were combined and washed with 2×40 mL of brine. The extract was concentrated under vacuum. This resulted in 500 mg (82%) of N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.42 (q, J=8.4 Hz, 1H), 7.37 (d, J=2 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 4.72 (q, J=13.6 Hz, 1H), 4.12 (t, J=6.4 Hz, 1H), 3.69 (s, 2H), 2.22-2.15 (m, 4H), 2.10-1.95 (m, 4H), 1.54 (d, J=6.8 Hz, 3H) ppm. LCMS (method A, ESI): RT=0.93 min, m/z=364.0 [M+H]⁺.

Step 6: Synthesis of benzyl 4-[[(1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate

Into a 100-mL 3-necked round-bottom flask was placed N,N-dimethylformamide (10 mL), N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (250 mg, 0.79 mmol, 1.00 equiv), and TEA (231 mg, 3.00 equiv). This was followed by the addition of a solution of benzyl 4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (657 mg, 1.98 mmol, 2.50 equiv) in 2 ml N,N-dimethylformamide which was added dropwise with stirring at −20° C. The resulting solution was stirred for 30 min at −20° C. The mixture was allowed to react, with stirring, for an additional 15 h at room temperature. The mixture was diluted with 50 mL of EA and washed with 2×20 mL of water and 2×20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The residue was chromatographed on a silica gel column with dichloromethane/methanol (20:1). This resulted in 60 mg (12%) of benzyl 4-[[(1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as a white solid. LCMS (method B, ESI): RT=1.43 min, m/z=611.0 [M+H]⁺.

Step 7: Synthesis of benzyl 4-[[(1R,3r,5S)-3-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-amido]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate

Benzyl 4-[[(1R,3r,5S)-3-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (60 mg) was purified by Chiral-Prep-HPLC with the following conditions (Chiral HPLC): Column, CHIRALPAK IA; mobile phase, MTBE:EtOH=50:50; Detector, 254 nm. This resulted in 28 mg (47%) of benzyl 4-[[(1R,3r,5S)-3-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as a white solid. ee value: 100%

Step 8: Synthesis of (2R)-2-methyl-3-oxo-N-[(1R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide Hydrochloride

Into a 50-mL round-bottom flask was placed benzyl 4-[[(1R,3r,5S)-3-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (28 mg, 0.05 mmol, 1.00 equiv) and hydrochloric acid (12N, 10 mL). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was washed with 2×10 mL of DCM and the aqueous layer concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep_HPLC_MC5): Column, X Select C18, 19*250 mm, 5 um; mobile phase, Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 23% B to 42% B in 11.5 min; Detector, 254 nm. The resulting fractions were concentrated under vacuum. The solids were dissolved in 2 ml hydrochloric acid (12 N) and again concentrated under vacuum. This resulted in 4.9 mg (21%) of (2R)-2-methyl-3-oxo-N-[(1R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide hydrochloride as a white solid. ¹HNMR (400 MHz, D₂O) δ: 7.32 (d, J=8 Hz, 1H), 7.21 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 4.79-4.72 (m, 1H), 4.21 (s, 2H), 4.04 (s, 1H), 3.37 (d, J=12.8 Hz, 2H), 3.20 (d, J=6.4 Hz, 2H), 2.95 (t, J=10.4 Hz, 2H), 2.25-2.15 (m, 3H), 2.14-2.00 (m, 6H), 1.95 (d, J=14.8 Hz, 2H), 1.65-1.40 (m, 5H) ppm. LCMS (method A, ESI): RT=1.49 min, m/z=477.3[M−HCl+H]⁺.

Example 13 Synthesis of N-[(1R,3r,5S)-8-[4-(benzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide (Cpd. No. 587)

Step 1: Synthesis of tert-butyl (1R,3r,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 250-mL 3-necked round-bottom flask was placed tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (5 g, 22.09 mmol, 1.00 equiv), water (100 mL), and NaHCO₃ (4.83 g, 149.50 mmol, 2.60 equiv). The solution was cooled to 0° C. and 2,2,2-trichloroethyl chloroformate (5.63 g, 26.57 mmol, 1.20 equiv) added dropwise over 10 mins. The resulting solution was stirred at room temperature overnight. The reaction mixture was extracted with 3×100 mL of dichloromethane and the organic layers combined. The combined extracts were washed with 3×100 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was washed with 3×100 mL of hexane. This resulted in 8.32 g (94%) of tert-butyl (1R,3r,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid. ¹H NMR (300 MHz, CDCl₃) δ: 5.30 (brs, 1H), 4.73 (s, 2H), 4.23 (brs, 2H), 4.00-3.89 (m, 1H), 2.30-2.17 (m, 2H), 2.12-2.03 (m, 2H), 1.90-1.80 (m, 2H), 1.78-1.69 (m, 2H), 1.46 (s, 9H) ppm. LCMS (method C, ESI): RT=1.27 min, m/z=386.0 [M+H−15]⁺.

Step 2: Synthesis of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate

Into a 250-mL round-bottom flask was placed tert-butyl (1R,3r,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (4 g, 9.96 mmol, 1.00 equiv) and dichloromethane (40 mL). To this hydrogen chloride (gas) was introduced. The resulting solution was stirred for 1 h at room temperature. The mixture was then concentrated under vacuum. This resulted in 3.3 g (98%) of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate hydrochloride as a white solid. ¹H NMR (300 MHz, D₂O) δ: 4.72 (s, 2H), 4.09 (brs, 2H), 3.83-3.75 (m, 1H), 2.28-1.95 (m, 8H) ppm.

Step 3: Synthesis of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate

Into a 25-mL round-bottom flask was placed 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate hydrochloride (1.0 g, 2.96 mmol, 1.00 equiv) and dichloromethane (15 mL). This was followed by the addition of TEA (1.5 g, 14.82 mmol, 5.01 equiv) dropwise with stirring at 0° C. To this was then added tert-butyl N-[1-(chlorosulfonyl)piperidin-4-yl]carbamate (1.8 g, 6.02 mmol, 2.04 equiv) in several batches at 0° C. The resulting solution was stirred for 14 h at 20° C. The reaction mixture was diluted with 35 mL of dichloromethane and washed with 3×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 1.5 g (90%) of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 5.22 (brs, 1H), 4.75 (s, 2H), 4.46 (brs, 1H), 4.13 (brs, 2H), 4.01-3.95 (m, 1H), 3.70 (d, J=12.0 Hz, 2H), 3.58 (brs, 1H), 2.84 (t, J=11.2 Hz, 2H), 2.33-2.14 (m, 4H), 2.10-1.98 (m, 2H), 1.96-1.84 (m, 3H), 1.65-1.50 (m, 3H), 1.47 (s, 9H) ppm. LCMS (method D, ESI): RT=1.58 min, m/z=507.0 [M+H−56]⁺.

Step 4: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 100-mL round-bottom flask was placed 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (1.0 g, 1.77 mmol, 1.00 equiv), AcOH (15 mL), zinc (1.73 g, 26.45 mmol, 14.92 equiv) and water (1 mL). The resulting mixture was stirred for 1 h at 25° C. The mixture was then diluted with 30 mL of H₂O and the solids were filtered out. The pH was adjusted to 9 with sodium carbonate (aq. sat.). The resulting solution was extracted with 5×30 mL of dichloromethane and the organic layers combined. After concentration this resulted in 500 mg (73%) of tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a white solid. LCMS (method A, ESI): RT=1.08 min, m/z=333.0 [M+H−56]⁺.

Step 5: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (200 mg, 0.51 mmol, 1.00 equiv), dichloromethane (5 mL), 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (109 mg, 0.62 mmol, 1.20 equiv), EDCI (118 mg, 0.62 mmol, 1.20 equiv), and HOBT (104 mg, 0.77 mmol, 1.50 equiv). This was followed by the addition of TEA (260 mg, 2.57 mmol, 4.99 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at 20° C. The reaction mixture was then diluted with 10 mL of dichloromethane and was washed with 2×5 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 243 mg (86%) of tert-butyl N-[1-[(1R,3r,5S)-3-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a off-white solid. LCMS (method A, ESI): RT=1.27 min, m/z=448.0 [M+H−100]⁺.

Step 6: Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (241 mg, 0.44 mmol, 1.00 equiv) and dichloromethane (5 mL). To this hydrogen chloride (gas) was introduced. The resulting solution was stirred for 2 h at 15° C. The mixture was then concentrated under vacuum. This resulted in 200 mg (94%) of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide hydrochloride as a yellow solid. ¹H NMR (400 MHz, CD₃OD): 7.70 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 1H), 4.14 (s, 3H), 3.86 (d, J=13.2 Hz, 2H), 3.61 (s, 2H), 3.31-3.25 (m, 1H), 2.91 (t, J=12.4 Hz, 2H), 2.37-2.25 (m, 2H), 2.21-1.98 (m, 8H), 1.76-1.63 (m, 2H) ppm. LCMS (method A, ESI): RT=1.07 min, m/z=448.3 [M+H]⁺.

Step 7: Synthesis of N-[(1R,3r,5S)-8-[4-(benzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide

Into a 25-mL round-bottom flask was placed N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide hydrochloride (60 mg, 0.12 mmol, 1.00 equiv), methanol (5 mL), and benzaldehyde (13 mg, 0.12 mmol, 0.99 equiv). The mixture was stirred for 0.5 h at 20° C. To this NaBH₃CN (7.8 mg, 0.12 mmol, 1.00 equiv) was added in batches. The resulting solution was stirred for 2 h at 70° C. The reaction mixture was concentrated under vacuum. The residue was diluted with 5 mL of H₂O and extracted with 2×5 mL of dichloromethane. The organic layers combined and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; Detector, 254 nm. This resulted in 14.8 mg (18%) of N-[(1R,3r,5S)-8-[4-(b enzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide trifluoroacetic acid as a white solid. ¹H NMR (300 MHz, CD₃OD): 7.70 (d, J=7.8 Hz, 2H), 7.69-7.48 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 4.28 (s, 2H), 4.14 (s, 3H), 3.92 (d, J=12.6 Hz, 2H), 3.60 (s, 2H), 3.54-3.35 (m, 1H), 2.90 (t, J=13.2 Hz, 2H), 2.35-2.22 (m, 4H), 2.21-2.10 (m, 4H), 2.09-1.98 (m, 2H), 1.85-1.68 (m, 2H) ppm. LCMS (method A, ESI): RT=2.26 min, m/z=538.4 [M+H]⁺.

Example 14 Synthesis of N-[(1R,3r,5S)-8-[4-(benzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide Trifluoroacetate (Cpd. No. 592)

Step 1: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-(6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 25-mL round-bottom flask was placed 6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (170 mg, 0.80 mmol, 1.00 equiv), dichloromethane (10 mL), HOBT (216 mg, 1.60 mmol, 2.00 equiv), EDCI (306 mg, 1.60 mmol, 2.00 equiv), and tert-butyl N-1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-ylcarbamate (375 mg, 0.97 mmol, 1.20 equiv). This was followed by the addition of TEA (400 mg, 3.95 mmol, 5.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with 10 mL of dichloromethane and washed with 2×5 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3:1). This resulted in 300 mg (64%) of tert-butyl N-[1-[(1R,3r,5S)-3-(6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a red solid. LCMS (method C, ESI): RT=0.88 min, m/z=582.0 [M+H]⁺.

Step 2: Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide Hydrochloride

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-(6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (300 mg, 0.52 mmol, 1.00 equiv) and hydrogen chloride/dioxane (10 mL, saturated, this solution was made by introducing hydrogen chloride gas into 1,4-dioxane under 0° C. for 6 hours). The resulting solution was stirred for 4 h at room temperature. The mixture was then concentrated under vacuum. This resulted in 170 mg (64%) of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide hydrochloride as a red solid. LCMS (method A, ESI): RT=0.96 min, m/z=482.0 [M+H]⁺.

Step 3: Synthesis of N-[(1R,3r,5S)-8-[4-(b enzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide; trifluoroacetic Acid

Into a 25-mL round-bottom flask was placed N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide hydrochloride (50 mg, 0.10 mmol, 1.00 equiv), methanol (5 mL), and benzaldehyde (12.3 mg, 0.12 mmol, 1.20 equiv). The mixture was stirred for 0.5 h at 20° C. To the above NaBH₃CN (7.3 mg, 0.12 mmol, 1.20 equiv) was added in batches. The resulting solution was stirred for 1 h at 70° C. The reaction mixture was then concentrated under vacuum and the crude product purified by Prep-HPLC with the following conditions: Column: X Select C18, 19*250 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 5% B to 36% B in 12.5 min; Detector: 254 nm. This resulted in 28 mg (42%) of N-[(1R,3r,5S)-8-[4-(b enzylamino)piperidine-1-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxamide trifluoroacetate as a white solid. ¹H NMR (400 MHz, CD₃OD): 7.53-7.49 (m, 5H), 7.33 (s, 1H), 6.97 (s, 1H), 4.29 (s, 2H), 4.16 (s, 3H), 3.91 (d, J=12.8 Hz, 2H), 3.57 (s, 2H), 3.41-3.37 (m, 1H), 2.89 (t, J=10.8 Hz, 2H), 2.37-2.21 (m, 4H), 2.20-2.08 (m, 4H), 2.05-1.96 (m, 2H), 1.80-1.70 (m, 2H) ppm. LCMS (method A, ESI): RT=1.31 min, m/z=572.2 [M+H]⁺.

Example 15 Synthesis of 6-chloro-2-oxo-N-((1S,3r,5R)-8-((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide (Cpd. No. 595)

Step 1: Synthesis of tert-butyl (1R,3S,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 250-mL round-bottom flask, was placed water (120 mL). This was followed by the addition of tert-butyl (1R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 8.84 mmol, 1.00 equiv), sodium bicarbonate (1.92 g, 22.85 mmol, 2.59 equiv). To the mixture was added 2,2,2-trichloroethyl chloroformate (2.28 g, 10.76 mmol, 1.22 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 18 h at 20° C. The resulting solution was extracted with 3×150 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.16 g (crude) of tert-butyl (1R,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 4.75 (s, 2H), 4.25 (s, 2H), 4.00-3.90 (m, 1H), 2.29-2.00 (m, 4H), 2.89-2.71 (m, 4H), 1.45 (s, 9H) ppm.

Step 2: Synthesis of 2,2,2-trichloroethyl (1S,3r,5R)-8-aza-bicyclo[3.2.1]octan-3-ylcarbamate

Into a 100-mL round-bottom flask, was placed dichloromethane (20 mL), tert-butyl (1R,3S,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 4.98 mmol, 1.00 equiv). Then hydrogen chloride gas was introduced into mixture. The resulting solution was stirred for 12 h at 80° C. The resulting mixture was concentrated under vacuum. This resulted in 1.7 g (crude) of 2,2,2-trichloroethyl N-[(1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate as a yellow solid. LCMS (method D, ESI): RT=0.86 min, m/z=303.2 [M+H]⁺.

Step 3: Synthesis of benzyl 4-(((1S,3r,5R)-3-(2,2,2-trichloroethoxy)carbonylamino)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 100-mL round-bottom flask, was placed dichloromethane (30 mL), 2,2,2-trichloroethyl N-[(1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (2.4 g, 7.96 mmol, 1.00 equiv), TEA (3.2 g, 31.62 mmol, 3.97 equiv). Then benzyl 4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (4 g, 12.05 mmol, 1.51 equiv) was added by dropwise at 0° C. The resulting solution was stirred for 12 h at 10° C. The resulting mixture was washed with 3×30 mL of water and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 2.8 g (59%) of benzyl 4-[[(1R,3S,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 7.41-7.30 (m, 5H), 5.15 (s, 2H), 4.75 (s, 2H), 4.30-4.15 (m, 4H), 4.05-3.90 (m, 1H), 2.95-2.76 (m, 4H), 2.35-2.10 (m, 4H), 2.10-1.90 (m, 5H), 1.57 (s, 1H), 1.40-1.20 (m, 3H) ppm. LCMS (method D, ESI): RT=1.15 min, m/z=596.1 [M+H]⁺.

Step 4 2,2,2-trichloro ethyl (1S,3r,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-ylcarbamate Hydrochloride Salts

Into a 250-mL round-bottom flask, was placed benzyl 4-[[(1R,5S)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate (1.5 g, 2.51 mmol, 1.00 equiv). This was followed by the addition of hydrochloric acid (12 N, 140 mL) at 10° C. The resulting solution was stirred for 12 h at 50° C. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g (88%) of 2,2,2-trichloroethyl N-[(1R,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate hydrochloride as a yellow solid. LCMS (method D, ESI): RT=0.67 min, m/z=464.0 [M+H]⁺.

Step 5: Synthesis of 2,2,2-trichloro ethyl (1S,3r,5R)-8-((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-ylcarbamate

Into a 100-mL round-bottom flask, was placed dichloromethane (40 mL). This was followed by the addition of methanol (20 mL), 2,2,2-trichloroethyl N-[(1R,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]carbamate hydrochloride (300 mg, 0.60 mmol, 1.00 equiv), 4,4,4-trifluorobutanol (227 mg, 1.80 mmol, 3.00 equiv). Then NaBH₃CN (303 mg, 4.81 mmol, 8.00 equiv) was added into by batchwise. To the mixture was added acetic acid (1 mL). The resulting solution was stirred for 6 h at 10° C. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with eluent (PE/EtOAc=2/1 to 100% EtOAc). This resulted in 295 mg (86%) of 2,2,2-trichloroethylN-[(1R,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate as yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 4.75 (s, 2H), 4.30 (s, 2H), 4.02-3.95 (m, 1H), 3.10-3.02 (m, 2H), 3.00-2.95 (m, 2H), 2.58-2.50 (m, 2H), 2.32-1.78 (m, 17H), 1.60-1.48 (m, 2H) ppm. LCMS (method D, ESI): RT=0.97 min, m/z=572.0 [M+H]⁺.

Step 6: Synthesis of (1S,3r,5R)-8-((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-amine

Into a 100-mL round-bottom flask, was placed 2,2,2-trichloroethyl N-[(1R,3S,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (50 mg, 0.09 mmol, 1.00 equiv). This was followed by the addition of acetic acid (15 mL), water (1 mL) and Zn (90 mg). The resulting solution was stirred for 12 h at 10° C. The solids were filtered out. The pH value of the solution was adjusted to 8 with sodium carbonate (sat. aq.). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 25 mg (72%) of (1R,3S,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid. LCMS (method B, ESI): RT=1.24 min, m/z=398.0 [M+H]⁺.

Step 7: Synthesis of 6-chloro-2-oxo-N-((1S,3r,5R)-8-((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (10 mL), (1R,3S,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (50 mg, 0.13 mmol, 1.00 equiv), 6-chloro-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (46 mg, 0.22 mmol, 1.73 equiv), 1H-1,2,3-benzotriazol-1-ol (35 mg, 0.26 mmol, 2.06 equiv), EDCI (50 mg, 0.26 mmol, 2.07 equiv), TEA (0.3 mL). The resulting solution was stirred for 12 h at 10° C. The solids were filtered out. The resulting mixture was diluted with 10 mL of water. The resulting solution was extracted with of 2×10 mL dichloromethane and the organic layers combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude reside was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Prep Phenyl, 5 um, 19×150 mm; mobile phase, Water with 50 mmol ammonium bicarbonate and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm. This resulted in 5.7 mg (8%) of 6-chloro-2-oxo-N-[(1R,3S,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-2,3-dihydro-1H-indole-5-carboxamide as a light pink solid. ¹HNMR (300 MHz, CD₃OD): δ 7.32 (s, 1H), 6.95 (s, 1H), 4.30-4.10 (m, 3H), 3.35 (s, 2H), 3.10-2.90 (m, 4H), 2.50-2.40 (m, 2H), 2.40-1.90 (m, 15H), 1.85-1.70 (m, 2H), 1.51-1.35 (m, 2H) ppm. LCMS (method B, ESI): RT=1.67 min, m/z=591.1 [M+H]⁺.

Example 16 Synthesis of N-((1R,3r,5S)-8-(4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide Trifluoroacetate (Cpd. No. 622)

Step 1: Synthesis of tert-butyl (1R,3r,5S)-3-(2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 100-mL round-bottom flask was placed dichloromethane (50 mL), 2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxylic acid (1.5 g, 7.42 mmol, 1.00 equiv), tert-butyl (1R,5 S,7S)-7-amino-3-azabicyclo[3.3.2]decane-3-carboxylate (2.0 g, 7.86 mmol, 1.06 equiv), HATU (5.65 g), and TEA (2.25 g, 22.24 mmol, 3.00 equiv). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was washed with 3×50 ml, of H₂O. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column with PE:EA (1:1). This resulted in 3.0 g (92%) of tert-butyl(1R,5r,7S)-7-(2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamido)-3-azabicyclo[3.3.2]decane-3-carboxylate as a white solid. ¹HNMR (300 MHz, DMSO): δ 8.20-8.15 (m, 1H), 7.77 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.08-3.90 (m, 1H), 3.50-3.10 (m, 2H), 2.15-1.80 (m, 8H), 1.50-1.30 (m, 9H) ppm. LCMS (method C, ESI): RT=1.25 min, m/z=411.2 [M+H]⁺.

Step 2: Synthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide

Into a 100-mL round-bottom flask was placed a solution of tert-butyl (1R,3r,5S)-3-(2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 3.65 mmol, 1.00 equiv) in methanol (30 mL). Hydrogen chloride gas was introduced into the solution at 0° C. for 1 h. The resulting solution was stirred for another 1 h at 20° C. The mixture was then concentrated under vacuum. This resulted in 1.3 g (crude) of N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamide as a white solid. LCMS (method A, ESI): RT=0.80 min, m/z=311.2 [M+H]⁺.

Step 3: Synthesis of 2,2-difluoro-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)benzo[d][1,3]dioxole-5-carboxamide

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamide (900 mg, 2.90 mmol, 1.00 equiv) in THF (150 mL). This was followed by the addition of LiHMDS (1M in THF, 10 mL) dropwise with stirring at −60° C. To this was added 4-oxocyclohexane-1-sulfonyl chloride (700 mg, 3.56 mmol, 1.23 equiv) in portions at −60° C. The resulting solution was allowed to warm to room temperature and stirred for another 12 hours at 25° C. The resulting mixture was concentrated under vacuum. The residue was extracted with 3×60 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a C18 gel column with H₂O/CH₃CN=3:5. This resulted in 260 mg (19%) of 2,2-difluoro-N-[(1R,3rS,5S)-8-[(4-oxocyclohexane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2H-1,3-benzo[d][1,3]dioxole-5-carboxamide as a white solid. LCMS (method B, ESI): RT=1.08 min, m/z=471.0 [M+H]⁺.

Step 4: Synthesis of N-((1R,3r,5S)-8-(4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide Trifluoroacetate

Into a 250-mL round-bottom flask was placed methanol (130 mL), 2,2-difluoro-N-[(1R,3r,5S)-8-[(4-oxocyclohexane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2H-1,3-benzo[d][1,3]dioxole-5-carboxamide (200 mg, 0.43 mmol, 1.00 equiv), HCOONH₄ (1080 mg, 17.13 mmol, 40.29 equiv), and acetic acid (24 mg, 0.40 mmol, 0.94 equiv). Then NaBH₃CN (50 mg, 0.79 mmol, 1.87 equiv) was added batchwise. The resulting solution was stirred for 2 h at 20° C. The mixture was then concentrated under vacuum. The residue was slurried with 150 mL of EtOAc and then filtrated. The filtrate was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Detector, 254 nm. This resulted in 15.2 mg (6%) of N-[(1R,3r,5S)-8-[(4-aminocyclohexane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamide trifluoroacetic acid as a white solid. ¹H NMR (300 MHz, D₂O): δ 7.46-7.44 (m, 2H), 7.19 (d, J=6 Hz, 1H), 4.18 (s, 2H), 4.05 (t, J=6.0 Hz, 1H), 3.48-3.10 (m, 2H), 2.30-1.80 (m, 13H), 1.65-1.38 (m, 3H) ppm. LCMS (method D, ESI): RT=1.55 min, m/z=472.0 [M+H]⁺.

Example 17 Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-thiazole-3-carboxamide Hydrochloride (Cpd. No. 610)

Step 1: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethyl-1,2-thiazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane (10 mL), 5-ethyl-1,2-thiazole-3-carboxylic acid (44 mg, 0.28 mmol, 1.00 equiv), tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (100 mg, 0.34 mmol, 1.21 equiv), HOBT (52 mg, 0.38 mmol, 1.36 equiv)), and EDCI (150 mg, 0.79 mmol, 2.80 equiv). This was followed by the addition of a solution of triethylamine (80 mg, 0.79 mmol, 2.80 equiv) in dichloromethane (1 ml) which was added dropwise with stirring at 0° C. The resulting solution was stirred for 15 hours at 20° C. The reaction was quenched by the addition of 50 mL of water and extracted with 2×100 mL of dichloromethane. The organic layers were combined and washed with 1×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 120 mg (81%) of tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethyl-1,2-thiazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a solid. LCMS (method A, ESI): RT=1.61 min, m/z=528.0[M+H]⁺.

Step 2: Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-thiazole-3-carboxamide Hydrochloride

Into a 50-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethyl-1,2-thiazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (120 mg, 0.23 mmol, 1.00 equiv) and hydrogen chloride/dioxane (10 mL, saturated, this solution was made by introducing hydrogen chloride gas into 1,4-dioxane under 0° C. for 6 hours). The resulting solution was stirred for 3 hours at 20° C. The mixture was then concentrated under vacuum. This resulted in 57.8 mg (55%) of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-thiazole-3-carboxamide hydrochloride as a solid. ¹H NMR (300 MHz, D₂O) δ: 7.45 (s, 1H), 4.15-4.02 (m, 3H), 3.80-3.78 (m, 2H), 3.38-3.22 (m, 1H), 2.98-2.82 (m, 4H), 2.30-2.18 (m, 2H), 2.11-1.87 (m, 8H), 1.71-1.52 (m, 2H), 1.30-1.20 (m, 3H) ppm. LCMS (method A, ESI): RT=1.81 min, m/z=428.2 [M−HCl+H]⁺.

Example 18 Synthesis of N-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide Hydrochloride (Cpd, No. 609)

Step 1: Synthesis of 3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxylic Acid

Into a 100-mL round-bottom flask was placed methyl 3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxylate (1 g, 4.83 mmol, 1.00 equiv), methanol (15 mL), tetrahydrofuran (15 mL), and water (15 mL). This was followed by the addition of a solution of sodium hydroxide (386 mg, 9.65 mmol, 2.00 equiv) in 5 ml H₂O which was added dropwise with stirring at 0° C. The solution was stirred for 20 min at 0° C. in an ice/salt bath. The resulting solution was allowed to react, with stirring, for an additional 18 h at room temperature. The reaction mixture was then concentrated under vacuum. The residue was diluted with 50 mL of H₂O and The pH adjusted to 3-4 with hydrochloric acid (1 N). The resulting mixture was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and washed with 2×30 mL of water and 1×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under vacuum. This resulted in 850 mg (91%) of 3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxylic acid as a brown solid. ¹H NMR (300 MHz, CD₃OD) δ: 7.68 (q, J=8.4 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.68 (s, 2H) ppm. LCMS (method A, ESI): RT=1.01 min, m/z=194.0 [M+H]⁺.

Step 2: Synthesis of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate

Into a 100-mL round-bottom flask was placed dichloromethane (30 mL), 2,2,2-trichloro ethyl N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate hydrochloride (900 mg, 2.66 mmol, 1.00 equiv), and TEA (1.37 g, 13.54 mmol, 5.00 equiv). This was followed by the addition of a solution of tert-butyl N-[1-(chlorosulfonyl)piperidin-4-yl]carbamate (1.6 g, 5.35 mmol, 2.00 equiv) in 2 ml dichloromethane which was added dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at 10° C. The mixture was then washed with 3×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.1 g (73%) of 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 5.22 (s, 1H), 4.75 (s, 2H), 4.47 (s, 1H), 4.14 (s, 2H), 3.98 (d, J=6 Hz, 1H), 3.70 (d, J=12 Hz, 2H), 3.58 (s, 1H), 2.84 (t, J=11.2 Hz, 2H), 2.27-2.25 (m, 4H), 2.03 (d, J=10.8 Hz, 2H), 1.95-1.87 (m, 4H), 1.58 (s, 2H), 1.55-1.40 (m, 9H) ppm. LCMS (method C, ESI): RT=1.24 min, m/z=563.0 [M+H]⁺.

Step 3: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 100-mL round-bottom flask was placed 2,2,2-trichloroethyl N-[(1R,3r,5S)-8-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (1.1 g, 1.95 mmol, 1.00 equiv), Zn (1.9 g, 15.00 equiv), AcOH (15 mL), and water (1 mL). The resulting mixture was stirred for 3 h at 10° C. The solids were filtered out. The pH was adjusted to 8 with sodium carbonate (aq. sat.). The resulting solution was extracted with 4×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This resulted in 750 mg (crude) of tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a light yellow crude solid. LCMS (method C, ESI): RT=0.61 min, m/z=389.0 [M+H]⁺.

Step 4: Synthesis of tert-butyl (1-(((1R,3r,5S)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)piperidin-4-yl)carbamate

Into a 100-mL round-bottom flask was placed N,N-dimethylformamide (10 mL), 3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxylic acid (55 mg, 0.28 mmol, 1.10 equiv), EDCI (98 mg, 0.51 mmol, 2.00 equiv), HOBT (70 mg, 0.52 mmol, 2.00 equiv), and tert-butyl N-1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-ylcarbamate (100 mg, 0.26 mmol, 1.00 equiv). This was followed by the addition of TEA (131 mg, 1.29 mmol, 5.00 equiv) which was added dropwise with stirring at 0° C. The resulting solution was stirred for 15 h at 10° C. The reaction mixture was diluted with 10 mL of H₂O and extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on a silica gel column with dichloromethane/methanol (10:1). This resulted in 100 mg (69%) of tert-butyl N-[1-[(1R,3r,5S)-3-(3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as a white solid. LCMS (method A, ESI): RT=1.32 min, m/z=586.0 [M+Na]⁺.

Step 5: Synthesis of N-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide Hydrochloride

Into a 50-mL round-bottom flask was placed dichloromethane (10 mL) and tert-butyl N-[1-[(1R,3r,5S)-3-(3-oxo-3,4-dihydro-2H-1,4-benzo[1)][1,4]oxazine-6-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (100 mg, 0.18 mmol, 1.00 equiv). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 3 h at 10° C. The reaction mixture was then concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Prep_HPLC_MC5): Column, X Select C18, 19*250 mm, 5 um; mobile phase, A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 5% B to 36% B in 12.5 min; Detector, 254 nm. The isolated purified product was dissolved in 2 ml concentrated hydrochloric acid and this solution concentrated under vacuum. This resulted in 45.7 mg (52%) of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-3-oxo-3,4-dihydro-2H-1,4-benzo[b][1,4]oxazine-6-carboxamide hydrochloride as a white solid. ¹H NMR (400 MHz, D₂O) δ: 7.28 (q, J=8.4 Hz, 1H), 7.18 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.60 (s, 2H), 4.10-3.95 (m, 3H), 3.74 (d, J=13.2 Hz, 2H), 3.35-3.25 (m, 1H), 2.88 (t, J=12 Hz, 2H), 2.25-2.18 (m, 2H), 2.10-1.98 (m, 6H), 1.91 (d, J=14.8 Hz, 2H), 1.67-1.52 (m, 2H) ppm. LCMS (method A, ESi): RT=1.40 min, m/z=464.0 [M−HCl+H]⁺.

Example 19 Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-ethyl-1,2-thiazole-3-carboxamide Hydrochloride (Cpd. No. 605)

Step 1: Synthesis of ethyl 2-amino-4-oxohex-2-enoate

Into a 250-mL round-bottom flask was placed ethyl 2,4-dioxohexanoate (10 g, 58.08 mmol, 1.00 equiv), benzene (100 mL), CH₃COONH₄ (13.4 g, 173.84 mmol, 2.99 equiv), and acetic acid (10 mL). The resulting solution was stirred at 80° C. overnight. The reaction mixture was cooled and concentrated under vacuum. The residue was diluted with 200 mL of ice-water and the pH adjusted to 8 with Na₂CO₃ (aq. Sat.). The resulting mixture was extracted with 3×100 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 7 g (70%) of ethyl 2-amino-4-oxohex-2-enoate as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 5.92 (s, 1H), 4.36-4.30 (m, 2H), 2.49-2.44 (m, 2H), 1.28-1.24 (m, 3H), 1.14-1.11 (m, 3H) ppm.

Step 2: Synthesis of ethyl 5-ethyl-1,2-thiazole-3-carboxylate

Into a 250-mL round-bottom flask was placed ethyl 2-amino-4-oxohex-2-enoate (4 g, 23.37 mmol, 1.00 equiv), tetrahydrofuran (50 mL), and P₂S₅ (2.6 g, 11.70 mmol, 0.50 equiv). The mixture was stirred overnight at room temperature. Then the mixture was concentrated and the residue was dissolved in ethyl acetate (20 mL). This solution was cooled to 0° C. and H₂O₂ (30%, 10 mL) was added dropwise. The resulting mixture was stirred for 10 min at room temperature. To the mixture was added activated charcoal. After filtration, the filtrate was diluted with H₂O (20 mL). This was extracted with EA (20 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.44 g (56%) of ethyl 5-ethyl-1,2-thiazole-3-carboxylate as brown oil. LCMS (method A, ESI): RT=1.36 min, m/z=186.1 [M+H]⁺.

Step 3: Synthesis of 5-ethyl-1,2-thiazole-3-carboxylic Acid

Into a 100-mL round-bottom flask was placed ethyl 5-ethyl-1,2-thiazole-3-carboxylate (2.44 g, 13.17 mmol, 1.00 equiv), methanol (10 mL), water (10 mL), tetrahydrofuran (10 mL) and LiOH.H₂O (1.66 g, 39.56 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was then concentrated under vacuum. The residue was diluted with 30 mL of H₂O and extracted with 5×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.44 g (70%) of 5-ethyl-1,2-thiazole-3-carboxylic acid as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ : 7.63 (s, 1H), 3.04-2.96 (m, 2H), 1.42-1.19 (m, 3H) ppm. LCMS (method D, ESI): RT=1.09 min, m/z=158.2 [M+H]⁺.

Step 4: Synthesis of (2S)-tert-butyl 4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

Into a 250-mL round-bottom flask was placed 5-ethyl-1,2-thiazole-3-carboxylic acid (1.5 g, 9.54 mmol, 1.00 equiv), EDCI (2.92 g, 15.23 mmol, 1.60 equiv), 1H-1,2,3-benzotriazol-1-ol (2.1 g, 15.54 mmol, 1.63 equiv), dichloromethane (20 mL), and (2S)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (2.45 g, 11.43 mmol, 1.20 equiv). Then TEA (2.89 g, 28.56 mmol, 2.99 equiv) was added dropwise. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 30 mL of H₂O and extracted with 3×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a combi-flash with eluent (EA:PE=1/1). This resulted in 1.5 g of (2S)-tert-butyl 4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate as a brown oil. LCMS (method D, ESI): RT=1.60 min, m/z=376.1 [M+Na]⁺.

Step 5: Synthesis of (2S,4S)-tert-butyl 4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

tert-Butyl (2S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate (470 mg, 1.33 mmol, 1.00 equiv was purified by Chiral-Prep-HPLC with the following conditions: Column, CHIRALCEL OJ-3, mobile phase, Hex (0.2% IPA):EtOH=70:30; Detector, 254 nm. This resulted in 200 mg (43%) of tert-butyl (2S,4S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate as a yellow solid. ee value: 100%

Step 6: Synthesis of 5-ethyl-N-((2S,4S)-2-methylpiperidin-4-yl)-1,2-thiazole-3-carboxamide

Into a 25-mL round-bottom flask was placed tert-butyl (2S,4S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate (200 mg, 0.57 mmol, 1.00 equiv), dichloromethane (10 mL). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was then concentrated under vacuum. This resulted in 150 mg (91%) of 5-ethyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-thiazole-3-carboxamide hydrochloride as a white solid. LCMS (method C, ESI): RT=0.49 min, m/z=254.4 [M−HCl+H]⁺.

Step 7: Synthesis of tert-butyl 1-((2S,4S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidin-1-ylsulfonyl)piperidin-4-ylcarbamate

Into a 25-mL round-bottom flask was placed 5-ethyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-thiazole-3-carboxamide hydrochloride (150 mg, 0.52 mmol, 1.00 equiv) and dichloromethane (10 mL). Then TEA (260 mg, 5.00 equiv) added dropwise followed by tert-butyl N-[1-(chlorosulfonyl)piperidin-4-yl]carbamate (750 mg, 2.51 mmol, 4.85 equiv) which was added in several portions. The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under vacuum and the. residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 150 mg (56%) of tert-butyl N-[1-[(2S,4S)-4-(5-ethyl-1,2-thiazole-3-amido)-2-methylpiperidine-1-sulfonyl]piperidin-4-yl]carbamate as a yellow solid. LCMS (method C, ESI): RT=1.57 min, m/z=516.2 [M+H]⁺.

Step 8: Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-ethyl-1,2-thiazole-3-carboxamide Hydrochloride

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(2S,4S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-sulfonyl]piperidin-4-yl]carbamate (150 mg, 0.29 mmol, 1.00 equiv) and dichloromethane (10 mL). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 1 h at room temperature. The mixture was then concentrated under vacuum. This resulted in 90 mg (68%) of N-[(2S,4S)-1-(4-aminopiperidine-1-sulfonyl)-2-methylpiperidin-4-yl]-5-ethyl-1,2-thiazole-3-carboxamide hydrochloride as a white solid. ¹H NMR (300 MHz, D₂O) δ: 7.46 (s, 1H), 4.06-4.01 (m, 1H), 3.71-3.55 (m, 4H), 3.33-3.20 (m, 2H), 2.95-2.82 (m, 4H), 2.04-1.97 (m, 4H), 1.80-1.57 (m, 4H), 1.30-1.22 (m, 6H) ppm. LCMS (method A, ESI): RT=1.74 min, m/z=416.2 [M−HCl+H]⁺.

Example 20 Synthesis of N-((2S,4R)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-ethyl-1,2-thiazole-3-carboxamide (Cpd. No. 629)

Step 1: Synthesis of (2S,4R)-tert-butyl 4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

tert-Butyl (2S)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate (470 mg, 1.33 mmol, 1.00 equiv) was purified by Chiral-Prep-HPLC with the following conditions: Column: CHIRALCEL OJ-3-; mobile phase, Hex (0.2% IPA): EtOH=70:30; Detector, 254 nm. This resulted in 100 mg (21%) of tert-butyl (2S,4R)-4-(5-ethyl-1,2-thiazole-3-amido)-2-methylpiperidine-1-carboxylate as a yellow solid. ee value: 100%.

Step 2: Synthesis of 5-ethyl-N-((2S,4R)-2-methylpiperidin-4-yl)-1,2-thiazole-3-carboxamide

Into a 25-mL round-bottom flask was placed tert-butyl (2S,4R)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-carboxylate (100 mg, 0.28 mmol, 1.00 equiv) and dichloromethane (10 mL). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 1 h at room temperature. The mixture was concentrated under vacuum. This resulted in 70 mg (85%) of 5-ethyl-N-[(2S,4R)-2-methylpiperidin-4-yl]-1,2-thiazole-3-carboxamide hydrochloride as a white solid. LCMS (method C, ESI): RT=0.49 min, m/z=254.2 [M−HCl+H]⁺.

Step 3: Synthesis of tert-butyl 1-((2S,4R)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidin-1-ylsulfonyl)piperidin-4-ylcarbamate

Into a 25-mL round-bottom flask was placed 5-ethyl-N-[(2S,4R)-2-methylpiperidin-4-yl]-1,2-thiazole-3-carboxamide hydrochloride (70 mg, 0.24 mmol, 1.00 equiv) and dichloromethane (10 mL). TEA (120 mg) was added dropwise at 0° C. tert-Butyl N-[1-(chlorosulfonyl)piperidin-4-yl]carbamate (350 mg, 1.17 mmol, 4.85 equiv) was then added in several portions. The resulting solution was stirred for 2 h at room temperature. The mixture was then concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 70 mg (56%) of tert-butyl N-[1-[(2S,4R)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-sulfonyl]piperidin-4-yl]carbamate as a yellow solid. LCMS (method C, ESI): RT=1.54 min, m/z=538.2 [M+Na]⁺.

Step 4: Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-ethyl-1,2-thiazole-3-carboxamide

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(2S,4R)-4-(5-ethyl-1,2-thiazole-3-carboxamido)-2-methylpiperidine-1-sulfonyl]piperidin-4-yl]carbamate (70 mg, 0.14 mmol, 1.00 equiv) and dichloromethane (10 mL). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 1 h at room temperature. The mixture was then concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: X Bridge RP, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 45% B in 8 min; 254 nm. This resulted in 13.8 mg (24%) of N-[(2 S,4R)-1-(4-aminopiperidine-1-sulfonyl)-2-methylpiperidin-4-yl]-5-ethyl-1,2-thiazole-3-carboxamide as a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 7.57 (s, 1H) 4.40-4.25 (m, 1H), 4.25-4.15 (m, 1H), 3.67-3.62 (m, 3H), 3.30-3.15 (m, 1H), 3.06-3.00 (m, 2H), 2.89-2.79 (m, 3H), 1.98-1.85 (m, 5H), 1.80-1.58 (m, 2H), 1.51-1.40 (m, 1H), 1.40-1.36 (m, 6H) ppm. LCMS (method A, ESI): RT=1.68 min, m/z=438.1 [M+Na]⁺.

Example 21 Synthesis of N-((2S,4S)-1-(4-acetamidophenylsulfonyl)-2-methylpiperidin-4-yl)-2-oxoindoline-5-carboxamide (Cpd. No. 632)

Step 1: Synthesis of (2S)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate

Into a 1-L round-bottom flask was placed methanol (600 mL), HCOONH₄ (32 g, 507.45 mmol, 36.08 equiv) and tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (3 g, 14.07 mmol, 1.00 equiv). NaCNBH₃ (1.7 g, 27.05 mmol, 1.92 equiv) was added batchwise slowly at 0-5° C. The resulting solution was stirred for 16 hours at 25° C. The reaction mixture was then diluted with 250 mL of ethyl acetate and washed with 3×250 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.5 g (83%) of tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylate as colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 4.13-4.11 (m, 1H), 3.98-3.97 (m, 1H), 3.49-3.28 (m, 2H), 2.24-2.10 (m, 2H), 1.76-1.75 (m, 2H), 1.45 (s, 9H), 1.27 (d, J=6.0 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.04 min, m/z=215.0 [M+H]⁺.

Step 2: Synthesis of (2S)-tert-butyl 4-(benzyloxycarbonylamino)-2-methylpiperidine-1-carboxylate

Into a 250-mL round-bottom flask was placed water (50 mL), tetrahydrofuran (50 mL), sodium carbonate (3.7 g, 34.91 mmol, 2.99 equiv), and tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylate (2.5 g, 11.67 mmol, 1.00 equiv). Then benzyl chloroformate (4 g, 23.45 mmol, 2.01 equiv) was added dropwise at 0-5° C. The resulting solution was stirred for 16 hours at 25° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 100 mL of ethyl acetate and washed with 3×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 2 g (49%) of tert-butyl (2S)-4-[[(benzyloxy)carbonyl]amino]-2-methylpiperidine-1-carboxylate as colorless oil. ¹H-NMR (300 MHz, CD₃OD) δ: 7.36-7.30 (m, 5H), 5.09 (s, 2H), 4.10-4.08 (m, 1H), 3.76-3.70 (m, 2H), 3.27-3.17 (m, 1H), 1.97-1.78 (m, 3H), 1.62-1.55 (m, 1H), 1.41 (s, 9H), 1.25 (d, J=8.0 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.57 min, m/z=349.3 [M+H]⁺.

Step 3: Synthesis of Benzyl (2S)-2-methylpiperidin-4-ylcarbamate

Into a 25-mL round-bottom flask was placed tert-butyl (2S)-4-[[(benzyloxy)carbonyl]amino]-2-methylpiperidine-1-carboxylate (400 mg, 1.15 mmol, 1.00 equiv) and dichloromethane (6 mL). Trifluoroacetic acid (3 mL) was then added dropwise at 0-5° C. The resulting solution was stirred for 30 min at 25° C. The mixture was concentrated under vacuum which resulted in 300 mg (crude) of benzyl N-[(2S)-2-methylpiperidin-4-yl]carbamate as a yellow liquid. LCMS (method A, ESI): RT=1.07 min, m/z=249.1 [M+H]⁺.

Step 4: Synthesis of benzyl (2S)-1-(4-acetamidophenylsulfonyl)-2-methylpiperidin-4-ylcarbamate

Into a 50-mL round-bottom flask was placed benzyl N-[(2S)-2-methylpiperidin-4-yl]carbamate (300 mg, 1.21 mmol, 1.00 equiv) and triethylamine (600 mg, 5.93 mmol, 4.00 equiv) in dichloromethane (30 mL). This was followed by the addition of 4-acetamidobenzene-1-sulfonyl chloride (720 mg, 3.08 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 16 hours at 25° C. The mixture was then concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/1). This resulted in 300 mg (56%) of benzyl N-[(2S)-1-[(4-acetamidobenzene)sulfonyl]-2-methylpiperidin-4-yl]carbamate as a yellow solid. LCMS (method D, ESI): RT=1.40 min, m/z=446.2 [M+H]⁺.

Step 5: Synthesis of N-(4-((2S)-4-amino-2-methylpiperidin-1-ylsulfonyl) phenyl)acetamide

Into a 50-mL round-bottom flask was placed benzyl N-[(2S)-1-[(4-acetamidobenzene)sulfonyl]-2-methylpiperidin-4-yl]carbamate (300 mg, 0.67 mmol, 1.00 equiv) and trifluoroacetic acid (10 mL). The resulting solution was stirred for 1 hour at 60° C. in an oil bath. The mixture was then concentrated under vacuum. This resulted in 280 mg (crude) of N-[4-[(2S)-4-amino-2-methylpiperidine-1-sulfonyl]phenyl]acetamide as yellow oil. LCMS (method D, ESI): RT=0.96 min, m/z=312.2 [M+H]⁺.

Step 6: Synthesis of N-(4-((2S,4S)-4-amino-2-methylpiperidin-1-ylsulfonyl)phenyl)acetamide and N-(4-(((2S,4R)-4-amino-2-methylpiperidin-1-yl)sulfonyl)phenyl)acetamide

N-[4-[(2S)-4-amino-2-methylpiperidine-1-sulfonyl]phenyl]acetamide (200 mg, 0.64 mmol, 1.00 equiv) was separated by Prep-SFC with the following conditions: Column, Lux 5u Cellulose-44.6*150 mm, 5 um Chiral-A (LUX-4); mobile phase, 25% IPA with MeOH; Detector, UV 254/220 nm. This resulted in 100 mg (100%) of N-[4-[(2S,4S)-4-amino-2-methylpiperidine-1-sulfonyl]phenyl]acetamide as a yellow solid and 40 mg (98%) of N-[4-[(2 S,4R)-4-amino-2-methylpiperidine-1-sulfonyl]phenyl]acetamide as a yellow solid. ee value: 100%.

Step 7: Synthesis of N-((2S,4S)-1-(4-acetamidophenylsulfonyl)-2-methylpiperidin-4-yl)-2-oxoindoline-5-carboxamide

Into a 10-mL round-bottom flask was placed 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (48 mg, 0.27 mmol, 2.00 equiv), 1-hydroxybenzotrizole (40 mg, 1.26 mmol, 2.00 equiv), triethylamine (50 mg, 0.49 mmol, 4.00 equiv), N-[4-[(2S,4S)-4-amino-2-methylpiperidine-1-sulfonyl]phenyl]acetamide (40 mg, 0.13 mmol, 1.00 equiv), and dichloromethane (4 mL). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol, 2.00 equiv) was added batchwise at 0-5° C. The resulting solution was stirred for 16 hours at 25° C. The mixture was then washed with 3×5 mL of brine and the organic layer concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol NH₄HCO₃ and CH₃CN (10.0% CH₃CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm. This resulted in 2.6 mg (4%) of N-[(2S,4S)-1-[(4-acetamidobenzene)sulfonyl]-2-methylpiperidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ: 7.84-7.78 (m, 4H), 7.74-7.71 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 3.95-3.90 (m, 2H), 3.62-3.51 (m, 1H), 3.33-3.32 (m, 2H), 3.15-3.04 (m, 1H), 2.19 (s, 3H), 2.06-1.98 (m, 1H), 1.93-1.88 (m, 1H), 1.73-1.68 (m, 2H), 1.40 (d, J=8.0 Hz, 3H) ppm. LCMS (method D, ESI): RT=2.62 min, m/z=471.2 [M+H]⁺.

Example 22 Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethylpyridazine-3-carboxamide Trifluoroacetate (Cpd. No. 616)

Step 1: Synthesis of 3-chloro-5-ethylpyridazine

Into a 50-mL round-bottom flask was placed 5-ethyl-2,3-dihydropyridazin-3-one (100 mg, 0.81 mmol, 1.00 equiv) and POCl₃ (5 mL). The resulting solution was stirred for 2 hours at 80° C. in an oil bath. The mixture was then concentrated under vacuum. The residue was extracted with 1×100 mL of dichloromethane and the organic layer washed with 50 mL of sodium bicarbonate (aq. sat.) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (30:100). This resulted in 80 mg (69%) of 3-chloro-54-ethylpyridazine as yellow oil. TLC, Rf=0.2 (PE:EA=10:1).

Step 2: Synthesis of methyl 5-ethylpyridazine-3-carboxylate

Into a 30-mL pressure tank reactor (100 mL) was placed 3-chloro-5-ethylpyridazine (80 mg, 0.55 mmol, 1.00 equiv), methanol (10 mL), triethylamine (112 mg, 1.11 mmol, 2.02 equiv), and Pd(dppf)Cl2 (148 mg). To the above CO (gas) was introduced and maintained at 30 atm. The resulting solution was stirred for 15 h at 80° C. The solids were filtered out. The filtrate was extracted with 2×100 mL of ethyl acetate and the organic layers combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (30:100). This resulted in 80 mg (86%) of methyl 5-ethylpyridazine-3-carboxylate as yellow oil. LCMS (method C, ESI): RT=0.78 min, m/z=167.0 [M+H]⁺.

Step 3: Synthesis of 5-ethylpyridazine-3-carboxylic Acid

Into a 10-mL round-bottom flask was placed methyl 5-ethylpyridazine-3-carboxylate 80 mg, 0.48 mmol, 1.00 equiv) and C₂H₅OH (5 mL). This was followed by the addition of a solution of LiOH.H₂O (100 mg, 2.4 mmol, 5.00 equiv) in water (1 mL) which was added dropwise with stirring at 0° C. The resulting solution was stirred for 3 hour at 20° C. The reaction was then quenched by the addition of 50 mL of water. The pH was adjusted to 5 with hydrochloric acid (6N). The mixture was extracted with 2×100 mL of dichloromethane and the combined organic layers dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 60 mg (34.7%) of 5-ethylpyridazine-3-carboxylic acid as black oil. LCMS (method D, ESI): RT=0.90 min, m/z=153.0 [M+H]⁺.

Step 4: Synthesis of tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethylpyridazine-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane 20 mL) and 5-ethylpyridazine-3-carboxylic acid (60 mg, 0.39 mmol, 1.00 equiv). To the above was added tert-butyl N-[1-[(1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (150 mg, 0.39 mmol, 0.98 equiv), HOBT (79 mg, 0.58 mmol, 1.49 equiv)), and EDCI (223 mg, 1.17 mmol, 2.99 equiv). This was followed by the addition of a solution of triethylamine (118 mg, 1.17 mmol, 2.99 equiv) in dichloromethane (2 ml) which was added dropwise with stirring at 0° C. over 3 min. The resulting solution was stirred for 15 hours at 20° C. The mixture was extracted with 2×100 mL of dichloromethane and the organic layers combined, washed with 50 mL of water and 50 mL of brine, and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50:100). This resulted in 50 mg (24%) of tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethylpyridazine-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate as yellow oil. LCMS (method D, ESI): RT=1.46 min, m/z=523.0 [M+H]⁺.

Step 5: Synthesis of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethylpyridazine-3-carboxamide Trifluoroacetate

Into a 25-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-(5-ethylpyridazine-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate (50 mg, 0.10 mmol, 1.00 equiv) and hydrogen chloride/dioxane (10 mL, saturated, this solution was made by introducing hydrogen chloride gas into 1,4-dioxane under 0° C. for 6 hours). The resulting solution was stirred for 4 h at 20° C. The mixture was then concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: X Select C18, 19*250 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 12% B to 52% B in 11.5 min; 254 nm. This resulted in 17.9 mg (35%) of N-[(1R,3r,5S)-8-(4-aminopiperidine-1-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethylpyridazine-3-carboxamide trifluoroacetate as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ: 9.29 (s, 1H), 8.19 (s, 1H), 4.37-4.28 (m, 1H), 4.21-4.11 (s, 2H), 3.86 (d, J=15.0 Hz, 2H), 3.30-3.20 (m, 1H), 2.99-2.80 (m, 4H), 2.45-2.30 (m, 2H), 2.18-2.00 (m, 8H), 1.79-1.61 (m, 2H), 1.40-1.29 (m, 3H) ppm. LCMS (method D, ESI): RT=1.27 min, m/z=423.2 [M+H]¹.

Example 23 Synthesis of 2-oxo-N-[1-[(piperidin-4-ylmethane)sulfonyl]piperidin-4-yl]-2,3-dihydro-1H-indole-5-carboxamide Trifluoroacetate (Cpd. No. 620)

Step 1: Synthesis of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic Acid

Into a 50-mL round-bottom flask was placed methyl 2-oxo-2,3-dihydro-1H-indole-5-carboxylate (800 mg, 4.18 mmol, 1.00 equiv) and methanol (10 mL). This was followed by the addition of a solution of NaOH (670 mg, 16.75 mmol, 4.00 equiv) in water (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at 20° C. The mixture was then concentrated under vacuum and the residue taken up in 20 mL of H₂O. This was washed with 2×5 mL of dichloromethane. The pH was adjusted to 4 with hydrochloric acid (1 N) and extracted with 5×50 mL of ethyl acetate and the organic layers combined. Concentration resulted in 592 mg (80%) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a yellow solid. ¹H NMR (400 MHz, DMSO) δ: 12.5 (brs, 1H), 10.7 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.54 (s, 2H) ppm. LCMS (method A, ESI): RT=0.97 min, m/z=178.0 [M+H]⁺.

Step 2: Synthesis of tert-butyl 4-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)piperidine-1-carboxylate

Into a 25-mL round-bottom flask was placed tert-butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.50 mmol, 1.00 equiv), dichloromethane (10 mL), 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (319 mg, 1.80 mmol, 1.20 equiv), EDCI (344 mg, 1.79 mmol, 1.20 equiv), and HOBT (304 mg, 2.25 mmol, 1.50 equiv). This was followed by the addition of TEA (454 mg, 4.49 mmol, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at 20° C. The solids were collected by filtration. This resulted in 393 mg (73%) of tert-butyl 4-(2-oxo-2,3-dihydro-1H-indole-5-amido)piperidine-1-carboxylate as a yellow solid. LCMS (method C, ESI): RT=0.78 min, m/z=304.0 [M+H−56]⁺.

Step 3: Synthesis of 2-oxo-N-(piperidin-4-yl)-2,3-dihydro-1H-indole-5-carboxamide Hydrochloride

Into a 25-mL round-bottom flask was placed tert-butyl 4-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)piperidine-1-carboxylate (250 mg, 0.70 mmol, 1.00 equiv) and hydrogen chloride/dioxane (3 mL, saturated, this solution was made by introducing hydrogen chloride gas into 1,4-dioxane under 0° C. for 6 hours). The resulting solution was stirred for 2 h at 20° C. The mixture was then concentrated under vacuum. This resulted in 200 mg (97%) of 2-oxo-N-(piperidin-4-yl)-2,3-dihydro-1H-indole-5-carboxamide hydrochloride as a light yellow solid. ¹H NMR (400 MHz, D₂O) δ: 7.65 (s, 2H), 6.95 (s, 1H), 4.04 (t, J=10.4 Hz, 1H), 3.54 (s, 2H), 3.42 (d, J=13.2 Hz, 2H), 3.12-3.01 (m, 2H), 2.13 (d, J=14.0 Hz, 2H), 1.81-1.65 (m, 2H) ppm. LCMS (method A, ESI): RT=0.89 min, m/z=260.0 [M+H]¹.

Step 4: Synthesis of benzyl 4-[[4-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)piperidine-1-sulfonyl]methyl]piperidine-1-carboxylate

Into a 50-mL round-bottom flask was placed 2-oxo-N-(piperidin-4-yl)-2,3-dihydro-1H-indole-5-carboxamide hydrochloride (80 mg, 0.27 mmol, 1.00 equiv) and NMP (16 mL). This was followed by the addition of TEA (82 mg, 0.81 mmol, 3.00 equiv) dropwise with stirring at 0° C. To this was then added benzyl 4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (135 mg, 0.41 mmol, 1.50 equiv) in several batches at 0° C. The resulting solution was stirred for 2 h at 20° C. The mixture was concentrated under vacuum. The residue was chromatographed on a silica gel column with dichloromethane/methanol (50:1-20:1). The collected fractions were combined and concentrated under vacuum. This resulted in 100 mg (67%) of benzyl 4-[[4-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)piperidine-1-sulfonyl]methyl]piperidine-1-carboxylate as a yellow solid. LCMS (method C, ESI): RT=1.04 min, m/z=555.0 [M+H]¹.

Step 5: Synthesis of 2-oxo-N-[1-[(piperidin-4-ylmethane)sulfonyl]piperidin-4-yl]-2,3-dihydro-1H-indole-5-carboxamide Trifluoroacetate

Into a 25-mL round-bottom flask was placed benzyl 4-[[4-(2-oxo-2,3-dihydro-1H-indole-5-carboxamido)piperidine-1-sulfonyl]methyl]piperidine-1-carboxylate (80 mg, 0.14 mmol, 1.00 equiv) and hydrochloric acid (12 N, 5 mL). The resulting solution was stirred for 2 h at 20° C. The mixture was then concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 43% B in 10 min; Detector: 254 nm. This resulted in 13.2 mg (17%) of 2-oxo-N-[1-[(piperidin-4-ylmethane)sulfonyl]piperidin-4-yl]-2,3-dihydro-1H-indole-5-carboxamide trifluoroacetate as a white solid. ¹H NMR (400 MHz, D₂O) δ: 7.61 (s, 2H), 7.00 (d, J=4.4 Hz, 1H), 4.00-3.90 (m, 1H), 3.75-3.66 (m, 2H), 3.60 (s, 2H), 3.43-3.37 (m, 2H), 3.15 (d, J=6.4 Hz, 2H), 3.05-2.92 (m, 4H), 2.31-2.18 (m, 1H), 2.15-1.97 (m, 4H), 1.69-1.50 (m, 4H) ppm. LCMS (method A, ESI): RT=1.03 min, m/z=421.1 [M+H]⁺.

Example 24 Synthesis of N-(azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide

Step 1: Synthesis of Ethyl 2-diazo-3-oxopropanoate

Oxalyl chloride (87.9 g, 693 mmol) was added to a cold solution of N,N-dimethylformamide (42.3 g, 578 mmol) in CHCl₃ (150 mL) and the reaction was stirred at room temperature for 30 min, followed by heating at 40° C. for a further 1 h. After chilling the reaction to −10° C., ethyl 2-diazoacetate (63.0 g, 552 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated and the residue was diluted with ether (200 mL), the solid was collected by filtration and dissolved in 10% aq. HOAc (200 mL), then stirred for a further 1 h. The resulting mixture was extracted with ethyl acetate (300 mL×3) and the organic was washed with saturated Na₂CO₃ aq. (300 mL) and brine (300 mL), dried over Na₂SO₄, filtered and concentrated to give crude ethyl 2-diazo-3-oxopropanoate (27 g, 32.8%) as red oil, which was used for next step without further purification. ¹H-NMR (400 MHz, CD₃OD) δ ppm: 9.67 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2, 3H).

Step 2: Synthesis of ethyl 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl 2-diazo-3-oxopropanoate (27 g, 189 mmol) in EtOH (100 mL) was added acetic acid (28.3 g, 472 mmol). Cyclopropanamine (10.7 g, 189 mmol) was added slowly and the mixture was stirred at room temperature overnight. The solvent was removed and saturated Na₂CO₃ aq. was added to the residue to bring the pH to 8. The mixture was extracted with ethyl acetate (200 mL×3), washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated. The resulting residue was purified by flash chromatography (PE:EA=2:1) to give crude ethyl 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (18.5 g, 54.0%) as yellow oil. ESI-LCMS (m/z): 182.2 [M+H]⁺.

Step 3: Synthesis of 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylic Acid

To a solution of ethyl 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (18.5 g, 102 mmol) in THF (80 mL)/H₂O (40 mL) was added lithium hydroxide hydrate (4.5 g, 107 mmol), the resulting mixture was stirred at room temperature for 3 hr. The solvent was removed and the residue was dissolved in H₂O (50 mL), extracted with EA (100 mL). The organic phase was discarded and the water phase was acidified with 2N HCl until the pH=5, The aqueous solution was extracted with DCM:MeOH=10:1 (1.5 L). The organic layer was dried and concentrated to afford 6.3 g of 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid as white solid. The aqueous layer was concentrated to afford another 11.4 g crude product, which was used for next step without further purification. ESI-LCMS (m/z): 154.1[M+H]⁺.

Step 4: Synthesis of tert-butyl 3-(1-cyclopropyl-1H-1, 2, 3-triazole-4-carboxamido)azetidine-1-carboxylate

A solution of 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (2 g, 13.0 mmol) in thionyl chloride (10 mL) was stirred at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Then the reaction residue was diluted with DMF (5 mL) and added dropwise to the solution of tert-butyl 3-aminoazetidine-1-carboxylate (2.23 g, 13.0 mmol) and DIPEA (4.19 g, 32.5 mmol) in DCM (15 mL) under 0° C. The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with ethyl acetate (200 mL), washed with water (10 mL×3) and brine (50 mL), dried over Na₂SO₄, filtered and concentrated. The resulting residue was purified by Flash chromatography (DCM:NH₃ in MeOH (7N)=100:050:1) to give tert-butyl 3-(1-cyclopropyl-1H-1,2,3-triazole-4-carboxamido)azetidine-1-carboxylate (3 g, 75.1%) as a yellow solid. ESI-LCMS (m/z): 252.2 [M−55]⁺.

Step 5: Synthesis of N-(Azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide

A solution of tert-butyl 3-(1-cyclopropyl-1H-1, 2,3-triazole-4-carboxamido)azetidine-1-carboxylate (3.0 g, 9.8 mmol) in HCl/MeOH (20 mL) was stirred at 50° C. for 2 h. After completion, the solvent was removed in vacuo. The residue was dissolved in NH₃/MeOH (7 mol/L, 20 mL) and stirred for 30 min. The solvent was removed and the residue was purified by Flash chromatography (DCM:NH₃ in MeOH (7N)=100:0˜30:1˜15:1) to give N-(azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (1.6 g, 80%) as a white solid. ESI-LCMS (m/z): 208.1 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD) δ ppm: 8.38 (s, 1H), 4.92-4.86 (m, 1H), 3.98-3.97 (m, 1H), 3.82-3.72 (m, 4H), 1.26-1.20 (m, 4H).

Example 25 Synthesis of 5-cyclopropylpyridazine-3-carboxylic Acid

Step 1: Synthesis of 5-cyclopropylpyridazin-3-ol

To a solution of 5-chloropyridazin-3-ol (1.0 g, 7.7 mmol) in toluene/H₂O (100:5, 50 mL) was added sequentially cyclopropylboronic acid (987 mg, 11.5 mmol), K₃PO₄ (4.51 g, 23.0 mmol), diacetoxypalladium (86.2 mg, 384 μmol) and tricyclohexylphosphine (107 mg, 384 μmol). The reaction mixture was stirred at 100° C. under N₂ atmosphere for 20 h. then concentrated in vacuum to remove the solvent Water (20 mL) was added and the solution was acidified with hydrochloric acid (4 M) to pH=3. The solution was extracted with EtOAc (200 mL×3) and the combined organic layer were washed with saturated NaCl solution, dried over Na₂SO₄, concentrated to give a brown residue then purified by silica-gel chromatography (PE:EA=1:1) to afford the desired product (350 mg, 34% yield) as white solid. ESI-LCMS (m/z): 137.1 [M+l]⁺.

Step 2: Synthesis of 3-chloro-5-cyclopropylpyridazine

A solution of 5-cyclopropylpyridazin-3-ol (350 mg, 2.6 mmol) in phosphorous oxychloride (10 mL) was stirred at 80° C. for 2 h. The remaining POCl₃ was removed under vacuum then the residue was cooled and added to 20 g of ice. The reaction mixture was neutralized with saturated NaHCO₃ solution and extracted with EtOAc (40 mL×3), the combined organic extract is washed with brine (100 mL×2), dried over Na₂SO₄ and the solvent is removed under vacuum. the resulting residue was purified by silica-gel chromatography (PE:EA=2:1) to afford the product 3-chloro-5-cyclopropylpyridazine as a colorless oil (200 mg, 50% yield). ESI-LCMS (m/z): 155.2 [M+1]⁺.

Step 3: Synthesis of ethyl 5-cyclopropylpyridazine-3-carboxylate

Potassium acetate (284 mg, 2.9 mmol) was added to a solution of 3-chloro-5-cyclopropylpyridazine (150 mg, 1.0 mmol) in ethanol (10 mL). The mixture was degassed, then Pd(dppf)Cl₂ (35.4 mg, 0.05 mmol) was added. The resulting mixture was heated under an atmosphere of CO at 70° C. for 20 hr. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=1:1) to obtain the desired product ethyl 5-cyclopropylpyridazine-3-carboxylate (100 mg, 54% yield, colorless oil). ESI-LCMS (m/z): 193.1 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 9.06 (d, J=2.4 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.39 (q, J=6.8 Hz, 2H), 2.11-1.92 (m, 1H), 1.34 (t, J=6.8 Hz, 3H), 0.96-0.93 (m, 2H).

Step 4: Synthesis of 5-cyclopropylpyridazine-3-carboxylic Acid

To a solution of methyl 5-cyclopropylpyridazine-3-carboxylate (185 mg, 1.03 mmol) in THF/H₂O (8 mL/2 mL) was added lithium hydroxide hydrate (64.6 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was adjusted to pH=5 with 1N HCl, then concentrated directly to 5-cyclopropylpyridazine-3-carboxylic acid (170 mg, 94.6%) as yellow solid and used in next step directly. ESI-LCMS (m/z): 165 [M+1]⁺.

Example 26 Synthesis of 2-(3-(1-(3-Aminoazetidin-1-yl)ethyl)-2-chlorophenoxy)ethan-1-ol

Step 1: Synthesis of 1-(2-chloro-3-methoxyphenyl)ethanol

A mixture of 2-chloro-3-methoxybenzaldehyde (2.38 g, 14 mmol) in THF (50 mL) was stirred at 0° C., and a solution of methylmagnesium bromide (5.6 mL, 16.7 mmol, 3M) in ether was added. The resulting mixture was stirred overnight. The reaction mixture was diluted with 1 N HCl (50 mL) and extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford 1-(2-chloro-3-methoxyphenyl)ethanol (2.60 g, 99.6%) as a yellow oil. ¹HNMR (400 MHz, CD₃OD) δ ppm: 7.49 (d, J=8.4 Hz, 1H), 6.90-6.85 (m, 2H), 5.25 (q, J=6.4, 12.8 Hz, 1H), 3.81 (s, 3H), 1.48 (d, J=6.4 Hz, 3H).

Step 2: Synthesis of 1-(2-chloro-3-methoxyphenyl)ethanone

A mixture of 1-(2-chloro-3-methoxyphenyl)ethanol (2.0 g, 10.7 mmol) and manganese(IV) oxide (4.65 g, 53.5 mmol) in DCM (50 mL) was heated to 40° C. and stirred overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford 1-(2-chloro-3-methoxyphenyl)ethanone (1.83 g, 89.8%) as a yellow oil. ESI-LCMS (m/z): 185.0 [M+1]⁺.

Step 3: Synthesis of 1-(2-chloro-3-hydroxyphenyl)ethanone

A mixture of 1-(2-chloro-3-methoxyphenyl)ethanone (540 mmol, 2.92 mmol) and aluminum trichloride (972 mg, 7.29 mmol) in monochlorobenzene (10 mL) was stirred at 120° C. for 2 hrs. After cooling to rt, the reaction mixture was added dropwise into 1N HCl in a water bath and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (PE:EA=5:1) to afford 1-(2-chloro-3-hydroxyphenyl)ethanone (400 mg, 80.3%) as a yellow solid ESI-LCMS (m/z): 171.0[M+H]⁺.

Step 4: Synthesis of 1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethanone

A mixture of 1-(2-chloro-3-hydroxyphenyl)ethanone (330 mg, 1.93 mmol), 2-bromoethanol (482 mg, 3.86 mmol) and K₂CO₃ (800 mg, 5.79 mmol) in DMF (10 mL) was heated to 80° C. overnight. Water was added and the mixture was extracted with ethyl acetate (30 mL×3), the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (DCM:MeOH=50:1) to afford 1-(2-chloro-3-(2-hydroxyethoxy) phenyl)ethanone (400 mg, 79.2%) as a yellow oil. ESI-LCMS (m/z): 251.1 [M+H]⁺.

Step 5: Synthesis of tert-butyl 1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-ylcarbamate

A mixture of 1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethanone (214 mg, 1 mmol), tert-butyl azetidin-3-ylcarbamate (206 mg, 1.20 mmol), acetic acid (120 mg, 2.00 mmol) and NaBH₃CN (125 mg, 2.00 mmol) in MeOH (10 ml) was stirred at 70° C. overnight. The reaction mixture was concentrated and adjusted pH=8-9 with a saturated solution of Na₂CO₃. The resulting mixture was extracted with DCM (30 mL×3) and the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep-TLC (DCM:MeOH=20:1) to afford tert-butyl (1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl) carbamate (220 mg, 52.7%) as a yellow oil. ESI-LCMS (m/z): 371.2 [M+l]⁺.

Step 6: Synthesis of 2-(3-(1-(3-Amino azetidin-1-yl)ethyl)-2-chlorophenoxy)ethanol

A mixture of tert-butyl (1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl and azetidin-3-yl)carbamate (200 mg, 539 μmol) in a solution of HCl/MeOH (10 mL, 3N) was stirred at rt for 3 hrs. The reaction mixture was concentrated under reduced pressure to afford 2-(3-(1-(3-amino azetidin-1-yl)ethyl)-2-chlorophenoxy)ethanol (120 mg, 68.9%) as a yellow oil. ESI-LCMS (m/z): 271.2 [M+l]⁺.

Example 27 Synthesis of (S)—N-(1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (Cpd. No. 831)

Step 1: Synthesis of N-(1-(1-(2-Chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid (22.9 mg, 150 μmol), 2 (3-(1-(3-aminoazetidin-1-yl)ethyl)-2-chlorophenoxy)ethanol (40.6 mg, 0.15 mmol), HATU (85.4 mg, 225 μmol) and DIPEA (38.6 mg, 300 μmol) in DMF (2 mL) was stirred at rt for 2 h. water was added and the mixture was extracted with ethyl acetate (10 mL×3), the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by Pre-TLC (DCM:MEOH=20:1) to afford N-(1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (15 mg, 24.6%) as a white solid. ESI-LCMS (m/z): 406.1 [M+23]⁺. ¹HNMR (400 MHz, CD₃OD) δ ppm: 8.38 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.00-6.93 (m, 2H), 4.66-4.59 (m, 1H), 4.06-3.95 (m, 4H), 3.89-3.86 (m, 2H), 3.83-3.79 (m, 1H), 3.53-3.50 (m, 1H), 3.22 (t, J=7.2 Hz, 1H), 3.04 (t, J=7.2 Hz, 1H), 1.30-1.19 (m, 7H).

Step 2: Synthesis of (S)—N-(1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide

N-(1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (350 mg, 862 μmol) was separated by chiral HPLC to obtain two single enantiomers, (isomer 1:160 mg, white solid, Ret time 5.02 min; isomer 2:170 mg, Ret time 6.51 min), absolute stereochemistry is undefined, the isomer (Ret time: 5.02 min) was assumed to be S configuration, (S)—N-(1-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)ethyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (160 mg, 45.8%) as a white solid. ESI-LCMS (m/z): 406.2 [M+1]⁺. ¹HNMR (400 MHz, CD₃OD) δ ppm: 8.38 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 6.99-6.94 (m, 2H), 4.63 (t, J=7.2 Hz, 1H), 4.06-3.98 (m, 4H), 3.89-3.86 (m, 2H), 3.82 (t, J=7.2 Hz, 1H), 3.52 (t, J=7.2 Hz, 1H), 3.22 (t, J=7.2 Hz, 1H), 3.05 (t, J=7.2 Hz, 1H), 1.27-1.21 (m, 7H). SFC conditions: Instrument: SFC-80 (Thar, Waters) t; Column: REGISCELL 20*250 mm, 5 um (Dacel); Column temperature: 35° C.; Mobile phase: CO₂/MEOH (0.2% methanol amina)=60/40: Flow rate: 80 g/min: Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 8.8 min; Sample solution: 350 mg dissolved in 15 ml Methanol; Injection volume: 3 mL.

Example 28 Synthesis of N-(1-((1-(4-Chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (Cpd. No. 985)

Step 1: Synthesis of 1-(4-Chlorobenzyl)-1H-pyrazole-4-carbaldehyde

To a solution of 1H-pyrazole-4-carbaldehyde (70 mg, 728 μmol) in MeCN (5 mL) was added 1-(bromomethyl)-4-chlorobenzene (149 mg, 728 μmol) and cesium carbonate (472 mg, 1.45 mmol). The mixture was stirred at r.t. for 2 h. The mixture was concentrated, diluted with EA and water. The organic phase was washed with brine (10 mL×2), dried over Na₂SO₄ and concentrated to give 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (162 mg, 101%) as a white solid, which was used in the next step without further purification. ESI-LCMS (m/z): 221[M+H]⁺.

Step 2: Synthesis of N-(1-((1-(4-Chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide

A mixture of N-(azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (62 mg, 299 μmol), 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (65.9 mg, 299 μmol), and sodium cyanoborohydride (56.3 mg, 897 μmol) in MeOH (10 mL) was stirred at 60° C. for 16 h. The mixture was cooled and concentrated. The residue was diluted with EA, washed with water (10 mL) and brine (10 mL×2), dried over Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (70 mg, 56.9%) as a white solid. ESI-LCMS (m/z): 412[M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 8.38 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 5.31 (s, 2H), 4.65-4.61 (m, 1H), 4.00-3.96 (m, 1H), 3.71-3.67 (m, 2H), 3.61 (s, 2H), 3.22 (t, J=8.0 Hz, 2H), 1.30-1.24 (m, 2H), 1.21-1.19 (m, 2H).

Example 29 Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylpyridazine-3-carboxamide (Cpd No. 929)

Step 1: Synthesis of tert-butyl (1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)carbamate

A mixture of 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (200 mg, 0.9063 mmol), tert-Butyl (azetidin-3-yl)carbamate hydrochloride (377 mg, 1.81 mmol) and acetic acid (54.4 mg, 0.9063 mmol) were dissolved in MeOH (40 ml). After stirred for 2 h at r.t., sodium cyanoborohydride (142 mg, 2.26 mmol) was added to the solution. The mixture was stirring over night at r.t. Then, the solution was concentrated under reduced pressure and the residue purified by flash column chromatography (eluant: DCM:MeOH=10:1 (600 ml)). To furnish tert-butyl (1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)carbamate (273 mg, 54.2%) as colorless oil. ESI-LCMS (m/z): 377 [M+H]⁺.

Step 2: Synthesis of 1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-amine

tert-Butyl (1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)carbamate (273 mg, 0.4908 mmol) was dissolved in HCl in MeOH (3M) (20 ml). The solution was stirring over night at 50° C. After cooled to r.t., the solution was concentrated to afford 1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-amine (200 mg, 71.7%) as yellow solid, which was used for next step without purification. ESI-LCMS (m/z): 277[M+H]⁺.

Step 3: Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylpyridazine-3-carboxamide

5-cyclopropylpyridazine-3-carboxylic acid (60 mg, 0.3654 mmol) and HATU (250 mg, 0.6577 mmol) were dissolved in DMF (6 ml). After stirred for 1 h at r.t., 1-(1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-amine (219 mg, 0.3836 mmol) and triethylamine (110 mg, 1.09 mmol) were added to the solution. Then, the mixture was stirring for 4 h at r.t. Then, ethyl acetate (100 ml) was added and the ethyl acetate layer was washed by brine (50 mL×1), dried by Na₂SO₄, and concentrated. The residue was purified by Prep-HPLC to afford N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylpyridazine-3-carboxamide (72 mg, 46.7%) as white solid. ESI-LCMS (m/z): 423[M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 9.15 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.36-7.32 (m, 2H), 7.20 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 4.72-4.68 (m, 1H), 3.74-3.70 (m, 2H), 3.63 (s, 2H), 3.30-3.26 (m, 2H), 2.12-2.08 (m, 1H), 1.33-1.28 (m, 2H), 1.04-1.00 (m, 2H).

Example 30 Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropylpicolinamide (Cpd. No. 930)

Step 1: Synthesis of tert-butyl 3-(4-bromopicolinamido)azetidine-1-carboxylate

To a solution of 4-bromopicolinic acid (10.0 mmol, 2.02 g), HATU (15.0 mmol, 5.7 g), HOAT (15.0 mmol, 2.04 g) and DIPEA (20.0 mmol, 2.58 g) in DMF (50 ml) was added tert-butyl 3-aminoazetidine-1-carboxylate (10.0 mmol, 1.72 g) and stirred at r.t. overnight. Added ethyl acetate (300 ml), washed with water (150 ml×6), dried over Na₂SO₄, concentrated and the residue was crystallized with ethyl acetate:petroleum ether=1:5 to give pale yellow powder (2.63 g, 74%). ESI-LCMS (m/z): 356 [M+H]⁺.

Step 2: Synthesis of tert-butyl 3-(4-cyclopropylpicolinamido)azetidine-1-carboxylate

To a solution of tert-butyl 3-(4-bromopicolinamido)azetidine-1-carboxylate (16.2 mmol, 5.8 g), cyclopropylboronic acid (32.4 mmol, 22.8 g), K₃PO₄ (48.5 mmol, 10.2 g) in dioxane (50 mL) was added Pd(dppf)Cl2 (1.61 mmol, 1.2 g). The mixture was degassed under reduced pressure while stirring and recharged with argon gas, this procedure was repeated for seven times and then heated to 100° C. overnight. The solvent was removed and the residue was purified by column chromatography (eluant: ethyl acetate:petroleum ether=1:3) to give tert-butyl 3-(4-cyclopropylpicolinamido)azetidine-1-carboxylate as a white solid (2.6 g, 50.5%). ESI-LCMS (m/z): 318 [M+H]⁺.

Step 3: Synthesis of N-(azetidin-3-yl)-4-cyclopropylpicolinamide

tert-Butyl 3-(4-cyclopropylpicolinamido)azetidine-1-carboxylate (1.1 g, 3.46 mmol) in 3N HCl in MeOH (50 ml) was stirred at room temperature for 16 h. LCMS showed the reaction was completed, the solvent was removed under reduced pressure, then NH₃ in MeOH (7N, 10 ml) was added and concentrated. The crude product was purified by flash column chromatography (40 g silica gel column, eluted with DCM:NH₃ in MeOH (7N)=10:1) to give the desired product N-(azetidin-3-yl)-4-cyclopropylpicolinamide (537 mg, 71.5%) as a white solid.

Step 4: Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropylpicolinamide

A mixture of N-(azetidin-3-yl)-4-cyclopropylpicolinamide (50 mg, 0.2301 mmol), 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (50.7 mg, 0.2301 mmol) and HOAc (34.5 mg, 0.6903 mmol) in MeOH (10 ml) was stirred at r.t. for 16 h. LCMS showed the reaction was completed, the solvent was removed under reduced pressure, NH₃ in MeOH (7N, 10 ml) was added and concentrated, the crude product, which was purified by Prep-TLC (eluant: DCM:NH₃ in MeOH (7N)=20:1) to give the desired product N-(1-(1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropylpicolinamide (30 mg, 30.9%) as a colorless oil. ESI-LCMS (m/z): 422[M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 8.44 (d, J=5.2 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 7.35-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.20 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 4.67-4.63 (m, 1H), 3.73-3.69 (m, 2H), 3.62 (s, 2H), 3.26-3.22 (m, 2H), 2.05-2.01 (m, 1H), 1.20-1.15 (m, 2H), 0.91-0.87 (m, 2H).

Example 31 Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (Cpd. No. 927)

Step 1: Synthesis of 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a solution of 5-cyclopropyl-1H-imidazole (5.16 g, 47.7 mmol) in anhydrous THF (50 mL) was added NaH (2.85 g, 71.5 mmol) portion-wise at 0° C. under nitrogen atmosphere and the mixture was stirred 0° C. for 0.5 h. To the reaction mixture was added SEM-Cl (11.9 g, 71.5 mmol) dropwise at 0° C. under nitrogen atmosphere and the mixture was stirred at 0° C. for 2 h. The mixture was concentrated in vacuo and the residue was purified with column chromatograph on silica gel (petroleum ether:ethyl acetate=2:1) to afford 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (2.10 g, 18.4%) as a yellow liquid. ESI-LCMS (m/z): 239[M+H]⁺.

Step 2: Synthesis of 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic Acid

Into the stirred solution of 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (400 mg, 1.7 mmol) in THF (20 mL) was added BuLi (0.7 mL, 2.5 M) at −70° C., the mixture was stirred at −70° C. for 1 h, then solid CO₂ was added at −70° C., stirred for the next 1 h, acidified with HCl (1 M). Concentrated in vacuum to obtained desired product (350 mg, yellow oil, Y: 74%). ESI-LCMS (m/z): 283[M+H]⁺.

Step 3: Synthesis of tert-butyl 3-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamido)azetidine-1-carboxylate

Into the stirred solution of 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic acid (350 mg, 1.23 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (316 mmol, 1.84 mmol) and HATU (700 mg, 1.84 mmol) in DMF (10 mL) was added DIPEA (478 mg, 3.7 mmol). The mixture was stirred at r.t. for 2 h. Concentrated in vacuum to remove the solvent, the residue was purified by Pre-TLC (petroleum ether:ethyl acetate 1:1) to afford tert-butyl 3-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamido)azetidine-1-carboxylate as a colorless oil (200 mg, 37%). ESI-LCMS (m/z): 437[M+H]⁺.

Step 4: Synthesis of N-(azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide

Into the stirred solution of tert-butyl 3-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamido)azetidine-1-carboxylate (200 mgn 0.5 mmol) in DCM (10 mL) was added TFA (444 mg, 4.6 mmol). The mixture was stirred at r.t. for 2 h. Concentrated in vacuum to remove the solvent to obtained the residue, basified with saturated NaHCO₃, extracted with EtOAc (30 mL×3), combined the organic layer, dried over Na₂SO₄, concentrated in vacuum to obtained the crude N-(azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide, which was used without further purification (80 mg, brown oil, Y: 84%). ESI-LCMS (m/z): 207[M+H]⁺.

Step 5: Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide

Into the stirred solution of N-(azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (400 mg, 1.9 mmol) and 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (425 mg, 1.9 mmol) in MeOH (20 mL) was added NaBH₃CN (600 mg, 9.6 mmol). The mixture was stirred at 60° C. for 20 h. The product was purified by reversed phase prep-HPLC (TFA, CH3CN:H2O 2O=5%-95%) to afford N-(1-(1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (49 mg, 6%). ESI-LCMS (m/z): 411[M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 7.92 (s, 1H), 7.67 (s, 1H), 7.36-7.34 (m, 2H), 7.24 (d, J=8.8 Hz, 2H), 6.91 (brs, 1H), 5.36 (s, 2H), 4.77-4.74 (m, 1H), 4.31-4.26 (m, 4H), 4.16-4.11 (m, 2H), 1.91-1.87 (m, 1H), 0.93-0.90 (m, 2H), 0.75-0.72 (m, 2H).

Example 32 Synthesis of 1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Cpd. No. 932)

Step 1: Synthesis of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde

To a mixture of 1H-pyrazole-4-carbaldehyde (100 mg, 1.04 mmol) and 1-(chloromethyl)-4-methoxybenzene (162 mg, 1.04 mmol) in CH₃CN (6 mL) was added potassium carbonate (287 mg, 2.08 mmol), the resulting mixture was stirred at reflux for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over Na₂SO₄ and concentrated to give 1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde (220 mg, 93.3%) as a colorless oil. ESI-LCMS (m/z): 217 [M+H]⁺.

Step 2: Synthesis of 1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4-carboxamide

To a mixture of N-(azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.2412 mmol) and 1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde (62.5 mg, 0.2894 mmol) in methanol (5 mL) was added acetic acid (724 μg, 0.01206 mmol), the mixture was stirred at r.t. for 15 min, then sodium cyanoborohydride (30.3 mg, 0.4824 mmol) was added, the resulting mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in aqueous solution of Na₂CO₃ and extracted with EtOAc (3×20 mL). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by prep-TLC (CH₂Cl₂/NH₃.MeOH=20/1) to give 1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4-carboxamide (53 mg, 53.9%) as a white solid. ESI-LCMS (m/z): 408[M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm: 8.39 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 6.90 d, J=8.4 Hz, 2H), 5.24 (s, 2H), 4.64-4.62 (m, 1H), 3.99-3.98 (m, 1H), 3.79 (s, 3H), 3.73-3.69 (m, 2H), 3.63 (s, 2H), 3.27-3.23 (m, 2H), 1.28-1.22 (m, 4H).

Example 33 SMYD3 Biochemical Assay

General Materials

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Tris, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. ³H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well opaque white OptiPlates and SPA beads (Perkin Elmer, catalog # RPNQ0013) were purchased from PerkinElmer.

Substrates

N-terminally GST-tagged MEKK2 (MAP3K2) protein corresponding to reference sequence AAF63496.3 was purchased from Life Technologies (catalog # PV4010). This protein was expressed in High Five insect cells and purified to >85% purity. Protein identity was confirmed by MS/MS analysis after proteolytic digestion. The protein sequence used was:

(SEQ ID No. 1) MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNK KFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERA EISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDR LCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCF KKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRH NQTSLYKKAGTMDDQQALNSIMQDLAVLHKASRPALSLQETRKA KSSSPKKQNDVRVKFEHRGEKRILQFPRPVKLEDLRSKAKIAFGQS MDLHYTNNELVIPLTTQDDLDKALELLDRSIHMKSLKILLVINGST QATNLEPLPSLEDLDNTVFGAERKKRLSIIGPTSRDRSSPPPGYIPDE LHQVARNGSFTSINSEGEFIPESMEQMLDPLSLSSPENSGSGSCPSL DSPLDGESYPKSRMPRAQSYPDNHQEFSDYDNPIFEKFGKGGTYPR RYHVSYHHQEYNDGRKTFPRARRTQGNQLTSPVSFSPTDHSLSTSS GSSIFTPEYDDSRIRRRGSDIDNPTLTVMDISPPSRSPRAPTNWRLG KLLGQGAFGRVYLCYDVDTGRELAVKQVQFDPDSPETSKEVNAL ECEIQLLKNLLHERIVQYYGCLRDPQEKTLSIFMEYMPGGSIKDQL KAYGALTENVTRKYTRQILEGVHYLHSNMIVHRDIKGANILRDST GNVKLGDFGASKRLQTICLSGTGMKSVTGTPYWMSPEVISGQGYG RKADIWSVACTVVEMLTEKPPWAEFEAMAAIFKIATQPTNPKLPP HVSDYTRDFLKRIFVEAKLRPSADELLRHMFVHYH.. Molecular Biology

Full-length human SMYD3 isoform 1 (BAB86333) was inserted into a modified pET21b plasmid containing a His6 tag and TEV and SUMO cleavage sites. Because two common variants of SMYD3 exist in the population, site directed mutagenesis was subsequently performed to change amino acid 13 from an asparagine to a lysine, resulting in plasmid pEPZ533. A lysine at position 13 conforms to the more commonly occurring sequence (NP_001161212).

Protein Expression

E. coli (BL21 codonplus RIL strain, Stratagene) were transformed with plasmid pEPZ553 by mixing competent cells and plasmid DNA and incubating on ice for 30 minutes followed by heat shock at 42° C. for 1 minute and cooling on ice for 2 minutes. Transformed cells were grown and selected on LB agar with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol at 37° C. overnight. A single clone was used to inoculate 200 mL of LB medium with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol and incubated at 37° C. on an orbital shaker at 180 rpm. Once in log growth, the culture was diluted 1:100 into 2 L of LB medium and grown until OD₆₀₀ was about 0.3 after which the culture was incubated at 15° C. and 160 rpm. Once OD₆₀₀ reached about 0.4, IPTG was added to a final concentration of 0.1 mM and the cells were grown overnight at 15° C. and 160 rpm. Cells were harvested by centrifugation at 8000 rpm, for 4 minutes at 4° C. and stored at −80° C. for purification.

Protein Purification

Expressed full-length human His-tagged SMYD3 protein was purified from cell paste by Nickel affinity chromatography after equilibration of the resin with Buffer A (25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol, pH7.8). The column was washed with Buffer B (Buffer A plus 20 mM imidazole) and His-tagged SMYD3 was eluted with Buffer C (Buffer A plus 300 mM imidazole). The His tag, TEV and SUMO cleavage sites were removed generating native SMYD3 by addition of ULP1 protein at a ratio of 1:200 (ULP1:SMYD3). Imidazole was removed by dialysis overnight in Buffer A. The dialyzed solution was applied to a second Nickel column and the native SMYD3 protein was collected from the column flow-through. The flow-through was dialyzed in Buffer D (25 mM Tris, 5% glycerol, 5 mM β-mercaptoethanol, 50 mM NaCl, pH7.8) and ULP1 was removed using a Q sepharose fast flow column. SMYD3 was eluted in Buffer A and further purified using an S200 size-exclusion column equilibrated with Buffer A. SMYD3 was concentrated to 2 mg/mL with a final purity of 89%.

Predicted Translation:

SMYD3 (Q9H7B4) (SEQ ID No. 2) MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSR GVVCDRCLLGKEKLMRCSQCRVAKYCSAKCQKKAWPDHKRECK CLKSCKPRYPPDSVRLLGRVVFKLMDGAPSESEKLYSFYDLESNIN KLTEDKKEGLRQLVMTFQHFMREEIQDASQLPPAFDLFEAFAKVIC NSFTICNAEMQEVGVGLYPSISLLNHSCDPNCSIVFNGPHLLLRAV RDIEVGEELTICYLDMLMTSEERRKQLRDQYCFECDCFRCQTQDK DADMLTGDEQVWKEVQESLKKIEELKAHWKWEQVLAMCQAIISS NSERLPDINIYQLKVLDCAMDACINLGLLEEALFYGTRTMEPYRIFF PGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIMRVTHG REHSLIEDLILLLEECDANIRAS.. General Procedure for SMYD3 Enzyme Assays on MEKK2 Protein Substrate

The assays were all performed in a buffer consisting of 25 mM Tris-Cl pH 8.0, 1 mM TCEP, 0.005% BSG, and 0.005% Tween 20, prepared on the day of use. Compounds in 100% DMSO (1 ul) were spotted into a 384-well white opaque OptiPlate using a Bravo automated liquid handling platform outfitted with a 384-channel head (Agilent Technologies). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD3, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40 ul) containing the SMYD3 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD3 for 30 min at room temperature, then a cocktail (10 ul) containing SAM and MEKK2 was added to initiate the reaction (final volume=51 ul). The final concentrations of the components were as follows: SMYD3 was 0.4 nM, ³H-SAM was 8 nM, MEKK2 was 12 nM, SAH in the minimum signal control wells was 1 mM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radiolabeled SAM (10 ul) to a final concentration of 100 uM, which dilutes the ³H-SAM to a level where its incorporation into MEKK2 is no longer detectable. Radiolabeled MEKK2 was detected using a scintillation proximity assay (SPA). 10 uL of a 10 mg/mL solution of SPA beads in 0.5 M citric acid was added and the plates centrifuged at 600 rpm for 1 min to precipitate the radiolabeled MEKK2 onto the SPA beads. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of ³H-labeled MEKK2 as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).

% Inhibition Calculation

${\%\mspace{14mu}{inh}} = {100 - {\left( \frac{{dpm}_{cmpd} - {dpm}_{m\; i\; n}}{{dpm}_{{ma}\; x} - {dpm}_{m\; i\; n}} \right) \times 100}}$

Where dpm=disintegrations per minute, cmpd=signal in assay well, and min and max are the respective minimum and maximum signal controls.

Four-Parameter IC50 Fit

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + \left( \frac{X}{{IC}_{50}} \right)^{{Hill}\mspace{14mu}{Coefficient}}} \right.}}$

Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.

SMYD3 biochemical assay data for representative Compounds of the Disclosure are presented in Tables 1A and 3A in the column titled “SMYD3 Biochem IC₅₀ (μM).”

Example 34 SMYD3 Cell Assay

Trimethyl-MEKK2-in-Cell Western Assay

293T/17 adherent cells were purchased from ATCC (American Type Culture Collection), Manassas, Va., USA. MEM/Glutamax medium, Optimem Reduced Serum medium, penicillin-streptomycin, 0.05% trypsin and 1×D-PBS were purchased from Life Technologies, Grand Island, N.Y., USA. PBS-10× was purchased from Ambion, Life Technologies, Grand Island, N.Y., USA. PBS with Tween 20 (PBST (10×)) was purchased from KPL, Gaithersburg, Md., USA. Tet System FBS-approved FBS US Source was purchased from Clontech, Mountain View, Calif., USA. Odyssey blocking buffer, 800CW goat anti-rabbit IgG (H+L) antibody, 680CW Goat anti-mouse IgG (H+L) and Licor Odyssey infrared scanner were purchased from Licor Biosciences, Lincoln, Nebr., USA. Tri-methyl-Lysine [A260]-MEKK2 antibody, MEKK2 and SMYD3 plasmids were made at Epizyme. Anti-flag monoclonal mouse antibody was purchased from Sigma, St. Louis, Mo., USA. Methanol was purchased from VWR, Franklin, Mass., USA. 10% Tween 20 was purchased from KPL, Inc., Gaithersburg, Md., USA. Fugene was purchased from Promega, Madison, Wis., USA. The Biotek ELx405 was purchased from BioTek, Winooski, Vt., USA. The multidrop combi was purchased from Thermo Scientific, Waltham, Mass., USA.

293T/17 adherent cells were maintained in growth medium (MEM/Glutamax medium supplemented with 10% v/v Tet System FBS and cultured at 37° C. under 5% CO₂.

Cell Treatment, in Cell Western (ICW) for Detection of Trimethyl-Lysine-MEKK2 and MEKK2.

293T/17 cells were seeded in assay medium at a concentration of 33,333 cells per cm² in 30 mL medium per T150 flask and incubated at 37° C. under 5% CO₂. Plasmids were prepared for delivery to cells by first mixing 1350 μL Opti-MEM with Fugene (81 μL) in a sterile Eppendorf and incubated for five minutes at room temperature (RT). MEKK2-flag (13.6 ug/T150) MEKK2 p3×Flag-CMV-14 with C-3×Flag and SMYD3 (0.151 ug/T150) SMYD3 p3×Flag-CMV-14 without C-3×Flag plasmids were aliquotted to a 1.7 mL sterile microfuge tube. The gene ID for MEKK2 and SMYD3 is NM 006609.3 and Q9H7B4, respectively. Entire volume of Opti-MEM/Fugene mixture was then added to a microfuge tube containing DNA plasmid, mixed and then incubated ×15 minutes at RT. The medium on the 293T/17 cells was refreshed, and the DNA/Fugene complex is added aseptically to each flask, rocked gently, and incubated at 37 C for 5 hours. Medium was then removed, and cells were washed once with PBS in the flask. Trypsin 0.05% (3 mL) was added and cells incubated for three minutes. Room temperature MEM+10% Tet system FBS was added and cells were mixed gently, and counted using the Vi-cell. Cells were seeded at 100,000 cells/mL in 50 μL MEM/10% Tet FBS/Pen/Strep to a 384 well black/clear poly-D-lysine coated plate containing test agent diluted in DMSO. The final top concentration of test compound was 40 μM. The total concentration of DMSO did not exceed 0.2% (v/v). Plates were incubated ×30 minutes at RT in low-airflow area, followed by incubation at 37° C. under 5% CO₂ for 24 hours. Medium was aspirated from all wells of assay plates prior to fixation and permeabilization with ice cold (−20° C.) methanol (90 μL/well) for ten minutes. Plates were rinsed with PBS three times on BioTek ELx405. PBS was removed with a final aspiration, and Odyssey blocking buffer (50 μL/well) was added to each well and incubated for one hour at RT. Primary antibody solution was prepared (anti-trimethyl-MEKK2 at 1:600 dilution plus mouse anti-flag antibody at 1:10,000 dilution in diluent (Odyssey Blocking buffer+0.1% Tween 20)) and 20 μL per well was dispensed using the Multidrop Combi. Assay plates were then sealed with foil, and incubated overnight at 4° C. Plates were washed five times with PBS-Tween (1×) on Biotek ELx405 and blotted on paper towel to remove excess reagent. Detection antibody solution (IRDye 800 CW goat anti-rabbit IgG diluted 1:400 in diluent (Odyssey Blocking buffer+0.1% Tween 20), plus IRDye 680CW goat anti-mouse IgG at 1:500 in diluent (Odyssey Blocking buffer+0.1% Tween 20) was added (20 μL/well) and incubated in dark for one hour at RT. Plates were then washed four times with PBS-T (1×) on ELx405. A final rinse with water was performed (115 μL/well×three washes on the ELx405). Plates were then centrifuged upside down, on paper towel, at 200×g to remove excess reagent. Plates were left to dry in dark for one hour. The Odyssey Imager was used to measure the integrated intensity of 700 and 800 wavelengths at resolution of 84 μm, medium quality, focus offset 4.0, 700 channel intensity=3.5 to measure the MEKK2-flag signal, 800 channel intensity=5 to measure the Trimethyl-MEKK2 signal of each well.

Calculations:

First, the ratio for each well was determined by:

$\left( \frac{{Trimethyl}\mspace{14mu}{MEKK}\; 2\mspace{14mu} 800\mspace{14mu}{nm}\mspace{14mu}{value}}{{flag}\mspace{11mu}{tagged}\mspace{14mu}{MEKK}\; 2\mspace{14mu} 700\mspace{14mu}{nm}\mspace{14mu}{value}} \right)$

Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells for maximum inhibition (Background). The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Reference compound was serially diluted two-fold in DMSO for a total of nine test concentrations, beginning at 40 μM. Percent inhibition was calculated (below).

${{Percent}\mspace{14mu}{Inhibition}} = {100 - \left( {\left( \frac{\left( {{Individual}\mspace{14mu}{Test}\mspace{14mu}{Sample}\mspace{14mu}{Ratio}} \right) - \left( {{Background}\mspace{14mu}{Avg}\mspace{14mu}{Ratio}} \right)}{\left( {{Minimum}\mspace{14mu}{Inhibition}\mspace{14mu}{Ratio}} \right) - \left( {{Background}\mspace{14mu}{Average}\mspace{14mu}{Ratio}} \right)} \right)*100} \right)}$

Non-linear regression curves were generated to calculate the IC₅₀ and dose-response relationship using triplicate wells per concentration of compound.

SMYD3 cell assay data for representative Compounds of the Disclosure are presented in Tables 1A and 3A in the column titled “SMYD3 Cell IC₅₀ (μM).”

Example 35 SMYD2 Biochemical Assay

General Materials

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), bicine, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. ³H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well streptavidin Flashplates were purchased from PerkinElmer.

Substrates

Peptide was synthesized with a N-terminal linker-affinity tag motif and a C-terminal amide cap by 21^(st) Century Biochemicals. The peptide was high high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS). The sequence was ARTKQTARKSTGGKAPRKQLATKAARKSA(K-Biot)-amide. (SEQ ID NO: 3)

Production of Recombinant SMYD2 Enzymes for Biochemical Enzyme Activity Assays

Full length SMYD2 (NP_064582.2) was cloned into a pFastbac-Htb-lic vector with an N-terminal His6 tag and FLAG tag, preceded by a TEV protease cleavage site. The protein was expressed in Sf9 insect cells. Cells were resuspended in lysis buffer (25 mM HEPES-NaOH, pH 7.5, 200 mM NaCl, 5% glycerol, and 5 mM (3-ME) and lysed by sonication. The protein was purified by Ni-NTA (Qiagen), followed by TEV cleavage to remove the His6 tag, subtractive Ni-NTA (Qiagen), and gel filtration chromatography using an S200 column (GE Healthcare). Purified protein was stored in 20 mM Tris-HCl, pH 8.0, 100 mM NaCl, and 1 mM TCEP.

General Procedure for SMYD2 Enzyme Assays on Peptide Substrates

The assays were all performed in a buffer consisting of 20 mM Bicine (pH=7.6), 1 mM TCEP, 0.005% Bovine Skin Gelatin, and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1 ul) were spotted into a polypropylene 384-well V-bottom plates (Greiner) using a Platemate Plus outfitted with a 384-channel head (Thermo Scientific). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD2, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40 ul) containing the SMYD2 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD2 for 30 min at room temperature, then a cocktail (10 ul) containing ³H-SAM and peptide was added to initiate the reaction (final volume=51 ul). The final concentrations of the components were as follows: SMYD2 was 1.5 nM, ³H-SAM was 10 nM, and peptide was 60 nM, SAH in the minimum signal control wells was 1000 uM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radioactive SAM (10 ul) to a final concentration of 600 uM, which dilutes the ³H-SAM to a level where its incorporation into the peptide substrate is no longer detectable. 50 ul of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the biotinylated peptides were allowed to bind to the streptavidin surface for at least 1 hour before being washed three times with 0.1% Tween20 in a Biotek ELx405 plate washer. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of ³H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).

% Inhibition Calculation

${\%\mspace{14mu}{inh}} = {100 - {\left( \frac{{dpm}_{cmpd} - {dpm}_{m\; i\; n}}{{dpm}_{{ma}\; x} - {dpm}_{m\; i\; n}} \right) \times 100}}$

Where dpm=disintegrations per minute, cmpd=signal in assay well, and min and max are the respective minimum and maximum signal controls.

Four-Parameter IC50 Fit

${\%\mspace{14mu}{inhibition}} = {{Bottom} + \frac{{Top} - {Bottom}}{\left( {1 + \left( {{IC}_{50}/\lbrack I\rbrack} \right)^{{Hill}\mspace{14mu}{Coefficient}}} \right)}}$

Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. I is the compound concentration.

SMYD2 biochemical assay data for representative Compounds of the Disclosure are presented in Tables 4A and 6A in the column titled “SMYD2 Biochem IC₅₀ (μM).”

Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated by reference herein in their entirety. 

What is claimed is:
 1. A compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is 1,2,3-triazolyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, (carboxamido)alkyl, (cycloalkyl)alkyl, optionally substituted C₃₋₁₂ cycloalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, aralkyl, —N(H)C(═O)R⁶, —C(═O)R⁷, and —S(═O)₂R⁸; each optionally substituted C₃₋₁₂ cycloalkyl is independently unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; each optionally substituted C₆₋₁₄ aryl is independently unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, (aralkyloxy)alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, heteroalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, (C₁₋₄ haloalkoxy)alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (carboxamido)alkyl-O—, mercaptoalkyl, (heterocyclo)alkyl, (heterocyclo)alkyl-O—, (cycloalkylamino)alkyl, (hydroxyalkylamino)alkyl, (amino)(heteroaryl)alkyl, (heterocycloamino)alkyl (amino)(hydroxy)alkyl, (heteroaryl)alkyl, (heteroaryl)alkyl-O—, —N(R⁴³)(R⁴⁴), —CH₂N(R⁴³)(R⁴⁴), —CH₂N(H)C(═O)—R⁴⁵, and —N(H)C(═O)—R⁴⁵; each optionally substituted 5- to 14-membered heteroaryl is independently unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), and —N(H)C(═O)—R⁴⁵, each optionally substituted 4- to 14-membered heterocyclo is independently unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl, Y is —C(═O)—; B is selected from the group consisting of C₃₋₁₂ cycloalkylenyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkenyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; and 4 to 14-membered heterocyclenyl, optionally substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl, with the proviso that B is not pyrrolidinenyl, optionally substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl; X is selected from the group consisting of —N(R³)—, —S(═O)₂—, —S(═O)₂N(R³)—, —N(R³)S(═O)₂—, —S(═O)₂C(R⁴)(H)—, —C(═O)—, —C(═O)N(R³)—, —N(R³)C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R⁴)(H)N(R³)—, —N(R³)C(═O)C(R⁴)(H)—, and —C(═O)C(R⁴)(H)—; or X is absent; Z is (heteroaryl)alkyl, wherein the heteroaryl is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), and —N(H)C(═O)—R⁴⁵; R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl; R⁶ is C₁₋₄ alkyl; R⁷ is C₁₋₄ alkyl; R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino, alkylamino, and dialkylamino; R⁴³ is hydrogen or C₁₋₄ alkyl; R⁴⁴ is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R⁴⁵ is alkyl; unsubstituted C₆₋₁₄ aryl; substituted C₆₋₁₄ aryl with one, two, three, four, or five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; unsubstituted C₅₋₁₄ heteroaryl; or substituted C₅₋₁₄ heteroaryl with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy, wherein —X—Z is attached to any available carbon or nitrogen atom of B.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula III, Formula IV, or Formula V:

wherein R^(10a), R^(10b), R^(11a), and R^(11b) are each independently selected from the group consisting of hydrogen and C₁₋₄ alkyl.
 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof having Formula VI, Formula VII or Formula VIII:

wherein: R^(12a), R^(12b), R^(13a), and R^(13b) are each independently selected from the group consisting of hydrogen and C₁₋₄ alkyl; X is selected from the group consisting of —C(═O)C(R⁴)(H)—, —C(═O)—, and —S(═O)₂—; and R⁴ is selected from the group consisting of hydrogen and amino.
 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula XV:

wherein R is selected from the group consisting of C₁₋₆ alkyl and C₃₋₁₂ cycloalkyl; and B is 4- to 14-membered heterocyclenyl, optionally substituted with one, two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is:

wherein the nitrogen atom is attached to —X—Z.
 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X is absent.
 7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Z is (heteroaryl)alkyl, wherein the heteroaryl is substituted with one, two, three or four substituents independently selected from the group consisting of aralkyl and (heteroaryl)alkyl.
 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula XVII:


9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula XVIII:

wherein: R′″ is selected from the group consisting of aralkyl and (heteroaryl)alkyl; and A is 1,2,3-triazolyl which is substituted with one substituent selected from the group consisting of C₁₋₆ alkyl and C₃₋₆ cycloalkyl.
 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein A is


11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is unsubstituted C₃₋₁₂ cycloalkylenyl.
 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is unsubstituted 4- to 14-membered heterocyclenyl.
 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is absent.
 14. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 15. A kit comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a patient having cancer.
 16. The kit of claim 15, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia adult T-cell lymphoma, aggressive natural killer-cell leukemia, acquired immunodeficiency syndrome-relaxed lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hem angioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, Liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, mucosa-associated lymphoid tissue lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
 17. A compound selected from the group consisting of: N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1-cyclopropyl-1H-1,2,3-triazole-4-carboxamide; and 1-cyclopropyl-N-(1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazole-4-carboxamide; or a pharmaceutically acceptable salt thereof. 